Smooth muscle of the bladder in the normal and the diseased state: Pathophysiology, diagnosis and treatment

ISSN 0163-7258/97 $32.00 PI1 SOl63-7258(97)00038-7

Phurmacol. Ther. Vol. 75, No. 2, pp. 77-110, 1997 Copyright 0 1997 Elsevier Science Inc. ELSEVIER

Smooth Muscle of the Bladder in the Normal and the Diseased State: Pathophysiology, Diagnosis and Treatment W. H . Turner ad A. F . Brading” UNlVERSITYDEPARTMENTOFPHARMACOLOGY,MANSFlELDROAD,OXFORDOX13QT,UK The smooth muscle of the normal bladder wall must have some specific properties. It must be very compliant and able to reorganise itself during filling and emptying to accommodate the change in volume without generating any intravesical pressure, but whilst maintaining the normal shape of the bladder. It must be capable of synchronous activation to generate intravesical pressure at any length to allow voiding. The cells achieve this through spontaneous electrical activity combined with poor electrical coupling between cells, and a dense excitatory innervation. In the diseased state, alterations of the smooth muscle may lead to failure to store or failure to empty properly. The diseased states discussed are bladder instability and diabetic neuropathy. Bladder instability is characterised urodynamically by uninhibitable rises in pressure during filling, and is seen idiopathically and in association with bladder outflow obstruction and neuropathy. In diabetic neuropathy, many of the smooth muscle changes are a consequence of diuresis, but there is evidence for alterations in the sensory arm of the micturition reflex. In the unstable bladder, additional alterations of the smooth muscle are seen, which are probably caused by the patchy denervation that occurs. The causes of this denervation are not fully established. Nonsurgical treatment of instability is not yet satisfactory; neuromodulation has some promise, but is expensive, and the mechanisms poorly understood. Pharmacological treatment is largely through muscarinic receptor blockade. Drugs to reduce the excitability of the smooth PHARMACOL. THER. muscle are being sought, since they may represent a better pharmacological option. 75(2):77-110, 1997. 0 1997 Elsevier Science Inc.

ABSTRACT.

KEY WORDS.

Urinary bladder, smooth muscle, diabetic neuropathy,

CONTENTS 1. INTRODUCTION.

.. . . . . . . . . . . 2. NORMALDETRUSOR. . . . . . . . . . 2.1. SPONTANEOUS SMOOTH MUSCLEACTIVITY . . . . . . . 2.2. IONCHANNELSCONTROLLING MEMBRANEANDACTION POTENTIALS . . . . . . . . . . 2.3. EXCITATORYINNERVATION. . 2.4. BLADDERSMOOTHMUSCLE CONTRACTION. . . . . . . . . 3. THEMICTURITION CYCLE 3.1. FILLING. . . . . . . . . . . . . 3.2. EMPTYING . . . . . . . . . . . 4. CLINICALMEASUREMENTOFBLADDER FUNCTIONANDCLINICALDISORDERSOF THEBLADDER. . . . . . . . . . . . . . 4.1. DEVELOPMENTOFHUMAN URODYNAMICS........... 4.2. CURRENTCLINICALURODYNAMIC TECHNIQUES :. . . . . . . . . 4.3. PROBLEMS WITHCLINICAL URODYNAMICS. . . . . . . . . 4.4. CLASSIFICATIONOFBLADDER DISORDERS . . . . . . . . . . . 5. THEUNSTABLEBLADDER .. . . . . . 5.1. THECLINICALCONDITION . . 5.1.1.HISTORY. . . . . . . . . . 5.1.2.SY~~PTOMS. . . . . . . . . 5.1.3.OCCURRENCE . . . . . . . 5.2. CLINICALEVIDENCEFORTHE AETIOLQGYOFDETRUSOR INSTABILITY . . . . . . . . . . 5.2.1.OBSTRUCTION AND AGE . 5.2.2.NEUROLOGICALFACTORS.

*Corresponding author.

. . 78 . . 78 . . 78

. . 79 . . 80

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. . 83 83

. . 83 . . 83 . . . . . .

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84 84 84 84 84 84

. . 85 . . 85 . . 85

detrusor, unstable bladder.

5.2.3. URINARY TRACT INFECTION . 5.2.4.LOWCOMPLIANCE. . . . . . . 5.3. EXPERIMENTAL INDUCTION OF BLADDERINSTABILITY. . . . . . . 5.3.1.MODELSOFOBSTRUCTIVE INSTABILITY. . . . . . . . . . 5.3.2.MODELSOFNONOBSTRUCTIVE INSTABILITY. . . . . . . . . . 6. DIABETICNEUROPATHY. .. . . . . . . . 6.1. THE CLINICALCONDITION. . . . . 6.2. EXPERIMENTAL INDUCTION OF DIABETICNEUROPATHY . . . . . . 7. FACTORSRESULTINGINALTERATIONSOF SMOOTHMUSCLEFUNCTION. . . . . . . . 7.1. HYPERTROPHYANDDIURESIS. . . 7.2. ALTERATIONS IN NEURONAL INPUT................ 7.2.1.DIABETICNEUROPATHY. . . . 7.2.2.PARTIALDENERVATION. . . . 7.3. THELINKBETWEENOBSTRUCTION ANDDENERVATION . . . . . . . . 8. SMOOTHMUSCLEINBLADDERSINTHE DISEASEDSTATE . . . . . . . . . . . . . . 8.1. OBSTRUCTEDBLADDER. . . , . . . . 8.1.1.EARLYOBSERVATIONS. . . . . 8.1.2.VARIABILITY OF THE RESULTS . . . . . . . . . . . . 8.1.3.CONTRACTILESTUDIES . . . . 8.1.4. ELECTRICALPROPERTIES . . . 8.1.5.STUDIES ON INTRACELLULAR CALCIUMSTORESAND INTRACELLULARFREE CALCIUMIONS. . . . . . . . . 8.2. CHANGESLEADINGTOBLADDER INSTABILITY.. . . . . . . . . . . . . 8.3. SMOOTHMUSCLEINTHE DIABETICBLADDER. . . . . . . . e .

85 85 85 86 86 86 86 87 87 87 88 88 88 89 89 89 89 90 90 91

91 92 92

W. H. Turner and A. F. Brading

78 9. TREATMENTOFTHE~NSTARLE

BLADDER .................. 9.1.INTRODUCTION. ........... 9.2.BEI-IAVIOURALANDELECTRICAL TREATMENTS.. ........... 9.3.DRUGTREATMENT. ......... 9.3.1. ATROPINE ........... 9.3.2. PROPANTHELINE........ 9.3.3. OXV~UTYNIN ......... 9.3.4. TERODILINE.......... 9.3.5. FLAVOXATE .......... 9.3.6. CALCIUM-CHANNEL

93 93 94 95

95 96 96 97 97

ANTAGONISTS . . . . . . . . 97 9.3.7. IMIPRAMINE.. . . . . . . . . 98 9.3.8. y_AMINOBUTYRICACID RECEI'TORAGONISTSAND ANTAGONISTS . . . . . . . . 98 9.3.9. POTASSIUM-CHANNEL AGONISTS. . . . . . . . . . . 98 9.3.10. DARIFENACINAND TOLTERODINE......... 99 9.4.SURGERY .............. 99 10. CONCLUSION. ............. 100 REFERENCES ................. 101

ACh, acetylcholine; [Ca*+li, intracellular free Ca *+ ions; GABA, yaminobutyric acid; IPj, inositol trisphosphate; KCO, K+-channel opener; STZ, streptozotocin; UTI, urinary tract infection.

ABBREVIATIONS.

1. INTRODUCTION The main component of the wall of the urinary bladder is smooth muscle-the detrusor. In the normal bladder, this smooth muscle is clearly of paramount importance in generating the pressure necessary to expel urine in the process of micturition. It needs, however, several unique properties in order that the bladder may function normally. To understand this requires a little thought about just what is required. Urine is produced continuously in the kidneys by reabsorption from, and secretion into, an ultrafiltrate of the blood. The filtration pressure is relatively low (about 25-40 cm HzO). It is an advantage to terrestrial animals for urine to be stored until a suitable time occurs when the bladder can be emptied. Thus, the bladder should be capable of storing a reasonable amount of urine. During bladder filling, however, it is imperative that the bladder pressure (intravesical pressure) does not rise above the filtration pressure, because this would prevent urine entering the bladder and allow back pressures to develop in the ureters, thus stopping filtration. The smooth muscle in the bladder wall, therefore, must be able to stretch and rearrange itself to allow an increase in bladder volume without significant pressure rise, in other words the bladder wall must be extremely compliant. Bladder emptying requires synchronous activation of all the smooth muscle, since if only part of the wall contracted, the uncontracted compliant areas would stretch and prevent the increase in pressure necessary for urine to be expelled through the urethra. It would also be an advantage to the animal for urination to be initiated and completed quickly. Rapid initiation requires that the shape of the bladder continuously conforms to the minimum surface area/volume ratio possible (as nearly spherical as is possible anatomically), since it is only when this condition is met that intravesical pressure will rise during synchronous smooth muscle contraction. This constraint means that there must be continuous contractile activity in the smooth muscle cells to adjust their length during filling (were the smooth muscle inactive during filling, the bladder would be floppy, and the shape distorted by the weight of the surrounding organs-this is never the case in a normal animal or human bladder). In the normal bladder, the smooth muscle possesses unique characteristics that permit these apparently contra-

dictory requirements to be fulfilled; it is exquisitely adapted to allow efficient storage of urine and to effect its rapid expulsion during micturition. In many diseased states, the behaviour or properties of the detrusor are altered, compromising normal function. Like all smooth muscles, the intrinsic properties of the detrusor, to a considerable extent, are determined or maintained by interaction with its normal extrinsic control pathways and its local environment. In diseased states, alterations in the properties of the detrusor often arise as a consequence of changes in these factors, and thus, are secondary to the disease; nevertheless, it is often the changes in detrusor properties that lead to the most distressing symptoms. Understanding the cellular changes that do occur could lead to the development of more effective drugs, which would have important therapeutic consequences because the quality of life of many patients could be immeasurably improved by the control of urinary tract symptoms. In this review, we first will describe what is known of the normal properties and control of the detrusor smooth muscle and the events of the micturition cycle. We then will discuss how detrusor function is assessed clinically and the most common types of disorders in which the properties of the detrusor are changed. We will discuss attempts, both clinical and using animal models, to investigate the aetiology of the unstable bladder and the changes associated with diabetes. We then will describe the results of investigations to assess functional

and structural changes

in the smooth

muscle that occur and might be responsible for the bladder dysfunction. Finally, we will discuss and evaluate the current treatments.

2. NORMALDETRUSOR 2.1. Spontaneous Smooth Muscle Activity Spontaneous contractile activity can be recorded in detrusor strips from all species, including humans, although the number of strips showing activity and the frequency of the contractions varies considerably between species (Sibley, 1984b; Mostwin, 1986; Brading and Williams, 1990). It seems probable that electrical activity in the form of action potentials underlies the contractile activity in all species, but micro-electrode recordings from intact smooth muscle strips have only been successfully undertaken on detrusor

Bladder Smooth Muscle in Health and Disease from

small

Mostwin,

79

such as guinea-pig

mammals,

1988; Fujii, 1988; Bramich

(Creed,

1971;

and Brading,

1996),

rabbit (Creed et al., 1983) , and rat (Hashitani 1995),

and combined

rarely undertaken

electrical

[but see Mostwin

(1985)

stock (1985),

and Fujii (1988)].

activity

Hoyle and Bum-

In these animals, spontane-

occur continuously.

(both electrical

The spontaneous

and mechanical)

in isolated strips

in all species can be shown to be myogenic, abolished activity

by receptor

antagonists

with tetrodotoxin.

recording

and double su-

crose gap records from Creed et al. (1983), ous action potentials

and Suzuki,

and mechanical

since it is not

or blockade

Spontaneous

of neuronal

action

have also been recorded with patch electrodes

potentials

in single hu-

ical activity Action

and K+-channel-blocking

potentials

An unusual feature of the spontaneous

mechanical

activ-

1990).

Kf-channel

the membrane

blockers

potential.

also have variable effects on

The evidence

through L-type Ca z+ channels, several types of K+ channel the membrane

that may be involved both in potential

(Brading

1985;

many preparations, Furthermore, frequency

of nearly zero tension,

individual

contractions

vary in size.

in detrusor smooth muscle, action potential

recorded from single cells in a strip may greatly

exceed that of the spontaneous In contrast, tential

and in

in intestinal

contractions

normally seen.

smooth muscle, each action po-

in one cell produces a small increase in tension

in

the whole strip, and above a critical frequency, the contractions fuse into a tetanus (Bulbring, nit contractions tively

poor

in detrusor strips suggests that there is rela-

electrical

cells, so spontaneous amongst

1955). The lack of teta-

them.

coupling electrical

between

smooth

muscle

activity spreads ineffectively

Experimental

measurements

of tissue im-

pedance in the guinea-pig support this, showing higher tis-

and Brading,

Isenberg

1993a,b;

and Klockner,

([Cal+],)

1993),

larisation,

function

Whole cell currents characteristic

1996).

Furthermore,

rarely

although

(Bramich

and Brading,

double-sucrose

gap record-

implications

and Brading,

delayed rectifier cur-

and Isenberg, 1985), current through Caz+K+

(Trivedi et al., 1995) and glib-

channels

(Bonev

An unusual feature of the electrical

and

Nelson,

activity of the

guinea-pig bladder is the sensitivity of the action potential frequency quency

to depolarisation.

can occur

Significant

in response

increases

membrane potential

electrical activity is not often resolved into clear spikes, and

known yet what the pacemaker

in the normal pig detrusor, the technique

does not work,

recent studies have demonstrated

probably because of insufficient

coupling

ised cells in the detrusor wall that are reminiscent

1988; Foster et al., 1989b).

This poor coupling is consistent

with the lack of gap junctions (Gabella

and Uvelius,

functional requirement

in detrusor smooth muscle

1990; Daniel et al.,

1983).

From a

point of view, these features match well with the that adjustments

in the length of the smooth

muscles can take place without produce synchronous

2.2.

(Fujii,

activation

the activity

spreading to

of the whole bladder wall.

mechanical

and electrical

mechanisms

It is not

are, although

the presence

of specialof the

interstitial cells of Cajal in the gut (Smet et al.,

199613). Another

relevant

stretch-activated

channels-these

feature is that the cells possess are nonselective

cation

channels,

and stretch thus will tend to depolarise the cells.

However,

the channels

have some permeability

ions, and their activation tion of the Ca*+-activated

to Ca!+

thus results in secondary activaK+ channels,

spond with a rapid depolarisation

and Action Potent&

The actions of channel-blocking

1986; Fujii, 1987).

in

which will modu-

late the response to stretch (Wellner and Isenberg, 1993a,b, 1994). This means that strips of smooth muscle will re-

ion Channels Controlling

Membrane

pacemaking

(Mostwin,

in fre-

to very small changes

ings can be made in some small mammal detrusor strips, the

electrical

1993a).

of those flowing through

myocytes, including voltage-sensitive rent (Klockner

1993a).

cells that are more than 40 pm

free Caz+ ions

several types of K+ channel have been identified in detrusor

impalements

between

and

but also show the unusual

(Nakayama

activated maxi K+ channels

only occurs

Gallegos

in guinea-pig bladder

a feature that may have important

for contractile

enclamide-sensitive

apart axially

and rat

property of being switched into a long open state by depo-

(Parekh et al., 1990; Fry et al., 1997). Dual microelectrode trical coupling

1993a)

by a rise in intracellular

(Nakayama,

and

in cells from hu-

and Fry, 1992;

Fry, 1994). The L-type Cal+ channels are inactivated

(Klockner

1985; Nakayama

Bonev and Nelson,

(Montgomery

This has

studies on isolated detrusor

(Edwards et al., 1991), and more recently, man detrusor

1996).

from the guinea-pig

sue impedance in the detrusor than in other smooth muscles of cells in guinea-pig detrusor show that elec-

and in action poten-

and Turner,

Isenberg,

and fall back to a baseline

flowing

and that the tissue contains

particularly

rise from

thus suggests that

the upstroke of the spike is produced by current

tial depolarisation

some

and some doing both (Fujii et al.,

myocytes,

normally

(Creed,

blocking drugs, some blocking after-hyperpolarisation, slowing depolarisation,

been confirmed by patch-clamp

contractions

it. are

1971)] is affected in various ways by different K+-channel-

tractions.

individual

bladder

phase and followed by an after-hyperpolarisation

ity in normal detrusor strips is the lack of fused tetanic conThe

drugs increase

from guinea-pig

blocked by L-type Ca *+-channel blockers (Mostwin, 1986), and their depolarisation phase [usually faster than the rising

determining

man detrusor myocytes.

recorded

and increase in action po-

tential frequency and force if the stretch is applied rapidly, drugs on the spontaneous

behaviour

of detrusor strips can

give some indication of the ion channels of functional importance. In detrusor strips from most animals studied, L-type Caz+-channel blockers reduce spontaneous mechan-

but the response

is transient,

and the tension

soon falls

back towards baseline. Slowly applied stretch does not activate

this contractile

response,

presumably

because

K+-

channel activation keeps up with opening of the stretchactivated channels, preventing the depolarisation. The

W. H. Turner and A. F. Brading

80

potential

for modulating

‘mechanogated’

ion channels

cently has been reviewed (Hamill and McBride,

re-

ing the voltage sufficient to elicit a just perceptible tion. Such curves for nonhuman

1996).

the right by tetrodotoxin 2.3.

is a dense excitatory

contrac-

are shifted to

and by desensitisation

of the PzX

purinoceptors, but unaffected by atropine (Sibley, 1984b; Brading and Williams, 1990). The shift in the curves when

Excitatory Innemmtion

There

mammals

innervation

of the detrusor in

humans and animals (Elbadawi and Schenk,

1966; Kltick,

nerve conduction tentials

1980). In the human, every smooth muscle cell is probably

sponses,

is blocked

in the intrinsic

shows that single action po-

nerves can elicit

contractile

and the shift with purinoceptor

within at most 200 nm of a nerve fibre (Daniel et al., 1983),

suggests that these are mediated by the purinoceptors

and the ratio of axons to detrusor cells in several animal

not the muscarinic

species is 1:l (Elbadawi and Schenk,

1995).

duration

of the

mammals and are not shifted by tetrodotoxin,

1966; Gabella,

This could permit virtually synchronous

activation

detrusor, either by direct nerve stimulation

of each cell or,

more likely, by very widespread nerve stimulation ited spread of action meagre electrical

potentials

enabled

by the detrusor’s

coupling.

via release of acetylcholine

(ACh)

of the detrusor

and ATP,

little evidence of separate cholinergic

but there is

and purinergic inner-

the two neurotransmitters

are thought

to be co-

with the lack of functional ley, 1984b).

The

purinoceptor

release of ACh

sor-in

rabbits, the phasic contraction

1985b;

Chen

et al.,

1994),

muscles do respond to bath-applied

although

the smooth

ATP, and it is probable

is activated jointly

by ACh and ATP, but the tonic contraction is mediated entirely by ACh (Levin et al., 1987). The phasic response to nerve stimulation

Mundy,

of the intrinsic

nerves can initiate a phasic and tonic response of the detru-

vitro can cause some expulsion

(SjBgren et al., 1982; Sibley, 198413; Kinder and

(Sib-

at eliciting contrac-

transmural field stimulation

sor excitatory neurotransmission, cholinergic

consistent

innervation

by single nerve stimuli

thus appears to be relatively ineffective

released (Hoyes et al., 1975; Brading, 1993). Human detruhowever, is probably purely

and

In the human, the strength

curves lie to the right of those for nonhuman

tion. Repetitive

In most species, there is dual excitation

vation;

and lim-

receptors.

re-

desensitisation

in the intact, but isolated, bladder in of urine, but is unable to

empty the bladder, and the same is true for activation

of pu-

with ATP (Levin et al., 1987). In contrast,

rinoceptors

tonic response to repetitive nerve stimulation

the

and the acti-

that ATP is released from the motor nerves. The lack of an

vation of the muscarinic receptors are both capable of pro-

effective

ducing complete

purinergic

innervation

could be due to a lack of

postsynaptic purinoceptors (Inoue and Brading, 1991). ACh activates detrusor cell membranes via muscarinic receptors. In small mammals, it causes little depolarisation the membrane Hashitani

(Callahan

and Creed,

and Suzuki, 1995),

although

1981;

Fujii,

it may cause a de-

layed increase in action potential frequency. Muscarinic ceptor

stimulation

has been shown

inositol trisphosphate

re-

to raise intracellular

(IP,) levels, implicating release of in-

tracellular stored Ca2* in the initiation ronha-Blob

of

1988;

of contraction

Selective

antagonist

of

by ATP, on the other hand, markedly de-

cells suggest that the functionally

response occurs (Marsh et al., 1996), potentially ing a further cellular mechanism

2.4.

Bladder Smooth Muscle

Estimations smooth

Stimulation junction

of the intrinsic

potentials

and Mostwin, zuki, 1995; (Fujii,

potentials

in small mammals (Fujii, 1988; Brading

Bramich

1988).

and Brading,

1996)

Under normal circumstances,

trigger action potentials,

L-type Cazf-channel

1990).

nerves results in depolarising

1989; Creed et al., 1994; Hashitani

blockers,

and Su-

of the active force that can be generated by the

ably large change

in cell length,

mum at filling volumes of 25-75% This allows emptying

these junction

large range of volumes.

potentials

can

Contraction concentration,

at will over a

muscles,

activation

involving

binding

1988) or blockade (Creed et al., 1994) of the PzXpurinocep-

nase, and phosphorylation

the myosin heads, leading to cross bridge cycling,

effects of intrinsic nerve stimulation

marised by Brading (1987)

evidence

would suggest that excitatory

junction

potentials

may be small, or absent, in the normal detrusor. Single electrical stimuli applied to detrusor strips can elicit a small contraction, and strength/duration curves can be constructed by varying the width of the pulse and find-

may be additional

of

of myosin light chain ki-

tor. No records have been made of the electrophysiological in the human, but the

calcium

through a sequence of events that probably

is shared by most smooth

(Fujii,

nearly maxi-

of the bladder capacity.

is triggered by a rise in intracellular

Ca2+ to calmodulin,

by desensitisation

1980)

over a remark-

remaining

to be accomplished

receptor

but abolished

and Gabella,

show that this remains reasonably constant

be recorded in isolation. They are unaffected by muscarinic blockade,

representof detrusor

Contraction

muscle cells in situ (Uvelius

and in the pig

but in the presence of

the junction

for regulation

contraction.

tential frequency

1988; Inoue and Brading,

important muscarinic re-

ceptors are of the M3 subtype (Harriss et al., 1995) and that after their stimulation, desensitisation of the resulting IP,

polarises the cells and causes a large increase in action po(Fujii,

scent marking.

studies with cultured human detrusor

(No-

et al., 1989; Iacovou et al., 1990). Activation

P,, purinoceptors

bladder emptying. In small mammals, the

phasic response may be of use in territorial

of the regulatory light chains of and Andersson

regulation

(1993a).

at the thin filaments,

as sumThere as re-

viewed recently (Horowitz et al., 1996). The Ca2+ source may be extracellular or intracellular Ca2+ stores (Mostwin, 1985; Brading, 1987; Maggi et al., 1989a). Bladder smooth muscle stores possess both ryanodine receptors (activated by

81

Bladder Smooth Muscle in Health and Disease

a rapid rise in free calcium concentration) (activated

and IP:, receptors

by IP3 produced as a result of agonist-stimulated

phosphoinositide

breakdown).

Intracellular

calcium release

can be triggered experimentally through activation of ryanodine receptors with caffeine (Ganitkevich and Isenberg, 1991)

or via the IP, mechanism

following

muscarinic receptors (Noronha-Blob al., 1990).

The link between

contraction

can occur with or without [electromechanical

activation

and its stimulus

cell membrane

depolarisation

coupling and pharmacomechanical

pling, respectively

(Somlyo,

of

et al., 1989; Iacovou et

1985)].

cou-

Both forms of coupling

can occur separately or together, and both can use extracellular or intracellular

calcium

sources (Andersson,

1993a).

The L-type Ca*+ channels can access the extracellular source either through action potentials continuous

Ca*+

or possibly through

Ca*+ leakage in the window of membrane

tentials at which there is low level, continuous tivity (Nakayama

and Brading,

1995).

channel

Action

Cal+,

to be an adequate stimulus for release

from the stores via ryanodine contraction

ac-

potentials

will result in transient rapid increases in intracellular and this is thought

po-

receptors.

How much of the

initiated by action potentials

is due to store re-

lease and how much by the Ca*+ carrying the inward current presently

is unclear.

Activation

of receptors can also

access both stores. PzX purinoceptors ion channels, Again,

the

and activating

the L-type Ca*+ chan-

rapid rise in intracellular

release Ca2+ from the stores via ryanodine carinic receptor activation, polarisation,

cat-

and these let in Cal+ ions, as well as depola-

rising the membrane nels.

are nonselective

Ca2+ could

receptors. Mus-

although not causing much de-

can also cause a small Ca*+ entry by activating

nonselective

cation

channels

through

G-proteins

(Inoue

and Brading, 1990), and also stimulates Ca2+ entry through L-type Caz,+ channels

by the increase

in spike frequency

that occurs. The increase in 1P3 that is also stimulated will release Ca*+ from the stores. The situation plicated by the fact that an increase from whatever source can modulate (e.g., inactivate channels,

L-type Ca2+ channels,

modulated

Ca2+ channels). tively labile-they

ryanodine,

is further com-

in intracellular ion channel

activate various K+

and IP,

receptor

store

The Ca*+ stores in the bladder are relacan be readily depleted in Caz+-free so-

lution and very rapidly filled from the extracellular (Mostwin,

Ca*+

function

1985). Exactly what mechanisms

source

are involved in

this exchange between stored and extracellular Ca2+ is unclear, although the stores can accumulate Ca2+ via a CaATPase. The relative importance of electromechanical and pharmacomechanical coupling and of intracellular or extracellular Cal+ sources in contraction of the human detrusor are unclear (Andersson, 1993a,b).

ment has been carefully studied in the guinea-pig by Uvelius and Gabella (1980). As the bladder wall becomes thin, so the number of muscle bundles in a section of the wall decreases. The muscle bundles become flatter, and the smooth muscle cells within a bundle become thinner, but can increase in length 4-fold, whilst keeping the same spatial relationship with their neighbours within the bundle. This reorganisation also has implications for the arrangement of the extracellular matrix, and particularly the collagen and elastin fibres. As described in Section 1, the detrusor does not fill as a floppy bag, but maintains tone during filling and thus, a minimum surface area to volume ratio, allowing efficient pressure generation when a contraction is eventually required. In the normal bladder, filling is achieved without a significant rise in intravesical pressure. Early studies (e.g., Mosso and Pellacini, 1882) of the control of the filling phase centred on bladder tone. ‘Tonus’ was assessed using the slope of a cystometrogram (a plot of the rise in pressure with time at a constant filling rate) corresponding to what is now defined urodynamically as compliance (Abrams et al., 1988). It was felt that a bladder with high tone (low compliance) would tolerate filling poorly and have a low capacity, and that a bladder with little tone (high compliance) would not empty adequately; regulation of tone, thereby, could control the filling phase. Considerable controversy has arisen over whether bladder tone is neurogenic or non-neurogenic. Denny-Brown and Robertson (1933a,b) regarded bladder capacity as a balance between “tonus” and “adaptation,” the latter being demonstrable as a slight pressure fall after each fill during incremental-fill cystometry, and interpreted as evidence of relaxation of reflex tone. Cystometry in patients with spinal injuries showed reduced tone, suggesting loss of basal neural tone (Holmes, 1933). However, studies of normal subjects, patients with spinal injuries, and dogs showed that tone, defined as the slope of the filling phase, was unaffected by either spinal anaesthesia or injury, spinal transection, or ganglion blockade, although these manoeuvres generally abolished micturition (Nesbit and Lapides, 1948; Plum, 1960; Plum and Colfelt, 1960). Recently, it has been shown that in patients with benign prostatic hyperplasia, the bladder wall compliance is significantly increased by urethral anaesthesia in patients with overactive, but not normal, bladders (Yokoyama et al., 1997), suggesting that there may be a neural component

to compliance

in

unstable bladders, but not in normal bladders. Furthermore, during filling m t h e anaesthetised cat, when the bladder was quiescent

between

phasic contractions,

there was no

pelvic nerve activity (de Groat and Ryall, 1969).

It seems

likely that much of the tone of the bladder is not neurally 3. THE 3.1.

MICTURITION

mediated,

CYCLE

Filling

The ability of the bladder wall to stretch sufficiently

but a property of the detrusor itself. This need

not imply a passive property of the bladder wall, and the sort of electrical smooth muscle properties mentioned in to ac-

commodate a reasonable amount of urine requires considerable reorganisation of the muscle bundles. This rearrange-

Section

2.1 could play an important role in regulating com-

pliance. The frequent spontaneous action potentials will produce localised contractile activity, tending to maintain

82

W. H. Turner and A. F. Brading

tone in the organ as a whole and to allow adjustment increase in volume (Stewart,

to the

1900), but poor electrical cou-

pling will prevent

synchronous

bladder, preventing

a build up of pressure. The stretch-acti-

vated channels

mentioned

ensure uniform adjustment volume-shortening

in Section

of the entire

2.2 presumably will

of the myocytes to the bladder

of a cell or bundle will switch off its

own stretch-stimulated noncontracting

contraction

channels

and simultaneously

stretch

neighbours and stimulate them.

in vitro and in vivo, and evidence suggests that there may be inhibitory Groat,

GABAergic

1990),

nerves acting not only centrally (de

but also in the periphery

Marchant,

1995).

There

inhibitory

synaptic

input onto the ganglion

A further factor that, theoretically,

could influence

the

filling phase is the release from the detrusor cells, during blocked with atropine, phentolamine, toprofen,

sidered. A population of sensory nerve endings in the blad-

field stimulation

der wall respond to filling (stretch) and contraction

sensitive, but the neurotransmitter

(Iggo, 1955; Morrison,

cells (Hoyle,

1994; Kataoka et al., 1994; Igawa et al., 1993).

cle, activity in the motor nerves to the muscle must be con-

receptors

and

for GABAergic

filling, of a relaxant substance. Human and pig detrusor strips,

In addition to the myogenic activity of the smooth mus-

tension

(Ferguson

is good evidence

[in series

1987a,b)].

Infor-

developed

relaxations

(Klarskov,

Field stimulation

propranolol,

in response

1987);

and ke-

to electrical

this was tetrodotoxincould not be identified.

of human detrusor strips, precontracted

mation mediated by these fibres will generate sensation and

with either K+ or carbachol, produced tetrodotoxin-resistant

also activate the afferent arm of the micturition

relaxations

pathways involved

in the micturition

(de Groat et al., 1993; Morrison,

reflex. The

reflex are complex

1987b,c;

Torrens,

1987b)

(James et al., 1993). They were reduced by ni-

tric oxide synthase inhibition abolished

with N-nitro-L-arginine,

by guanylate cyclase inhibition

and

with methylene

and beyond the scope of this review, but the final part of

blue, suggesting that they were at least partially caused by

the efferent

nitric

arm consists

of parasympathetic

rones in the sacral micturition through sacral roots 2-4,

motor

centre, whose axons emerge

and synapse with ganglia in the

pelvic plexus or bladder wall. The postganglionic densely innervate

Although

sacral micturition

neurones

the smooth muscle. Clearly, the ‘tone’ of

the bladder wall will be enhanced neurones.

neu-

by any activity in these

in the normal animal, activity centre

in the

during filling will be suppressed,

oxide and that this was generated

cells themselves. bethanecol,

by the detrusor

In foetal calf detrusor precontracted

field stimulation

mediated by

nitric oxide (Lee et al., 1994). The implication

is that if the

detrusor generates nitric oxide and this causes relaxation, could represent

a possible mechanism

ance. Support comes from the demonstration

of nitric oxide

synthase activity in detrusor cells (Weiss et al., 1994). Un-

and thus, supply little input onto the ganglion cells through

fortunately,

tently in the detrusor of either the human

larly in the later phases of filling. Yokoyama et al. (1997) have

1994) or the pig (Persson and Andersson,

subthreshold

the relaxations

could not be reproduced consis(Ehren

in the pig, there was some evidence of relaxation with myogenic

likely that there are other inputs to the ganglia. Capsaicin-

oxide donors produced very substantial relaxations

sensitive

nociceptive

nerves

with a joint

sensory-motor

are present in the bladder wall, and their activa-

tion can modulate micturition

in experimental

animals (for

a review, see Maggi and Meli, 1988). It has been shown that collaterals

from these neurones

may innervate

ganglia, ei-

and Andersson,

1992). More recently, relaxations

flexic

human detrusor have been compared

responses were inconsistent suggesting that hyperreflexia

Apart from excitatory

evidence that there are some inhibitory

neuronal pathways

that can influence bladder tone. Sympathetic

inhibition

the control

an abnormality involvement

between them.

input to the ganglia, there is good of

mediated

(Williams

et

al., 1995). As in most other studies of detrusor relaxations,

is evidence

and the possibility exists for interactions

nitric

(Persson

by myogenic release of nitric oxide in normal and hyperre-

between

there are different populations of cells (Smet et al., 1996a),

associated

nitric oxide release, and exogenous

ther in the bladder wall or in the pelvic plexus. Also, there that even within ganglia in the bladder wall,

et al.,

1992), although

sensory input from the prostatic urethra in males. It is also

function

it

of bladder compli-

this pathway, it is difficult to exclude some input, particualso suggested that there may be a continuous

with

caused relaxation

and small, and no difference

and hyperreflexic

tissues was found,

could not be accounted

of myogenic relaxation.

of nitric oxide in detrusor compliance

tractive hypothesis,

firm evidence

is an at-

is lacking. Another

didate to mediate detrusor relaxation working through Pzy purinoceptors

for by

Thus, although the can-

during filling is ATP, rather than the excita-

bladder activity via the hypogastric nerve, for instance, has been shown in the cat (Elliott, 1907; Satchel1 and Vaughan,

tory PzX receptors.

1988),

ation of the detrusor in small mammals (Bolego et al., 1995;

and at ganglionic

de Groat nervation

and Theobald, to the smooth

level (de Groat and Saum, 1972; 1976). muscle

Inhibitory

adrenergic

(Elbadawi

1966) does not occur in humans (Gosling,

in-

and Schenk,

1986),

and nei-

ther division nor stimulation of the hypogastric nerve in humans significantly affects bladder activity (Learmonth, 1931),

suggesting that any sympathetic

inhibition

of the

human bladder must occur at the ganglionic level or above. The system can also be influenced by pharmacological manipulation of y-aminobutyric acid (GABA) receptors, both

these receptors Boland

et al.,

It has been shown that activation

through 1993)

a G-protein

link mediates

and in primates

(McMurray

of

relaxet al.,

1997), and the suggestion is that ATP may be released from the detrusor during filling and act through extrasynaptic

re-

ceptors to mediate relaxation.

3.2.

Emptying

At the end of the filling phase, when a decision to initiate voiding is made, the inhibitory control of the spinal mictu-

83

Bladder Smooth Muscle in Health and Disease rition centre is switched off and activity initiated in the parasympathetic nerves. The density of the excitatory fibres insures that the smooth muscle cells are synchronously activated, leading to a rapid increase in intravesical pressure. In the whole animal, this is preceded by a drop in urethral luminal pressure, thus allowing micturition to proceed. In small animals, the release of ATP from the excitatory nerves mediates a rapid transient contraction through activation of the PzXpurinoceptors, which can be used alone for expulsion of some urine, e.g., for scent marking. Emptying the bladder seems to require continuous activation of the excitatory nerves, which can allow the development of a more prolonged ‘tonic’ contraction mediated through muscarinic receptors.

4. CLINICAL MEASUREMENT OF BLADDER FUNCTION AND CLINICAL DISORDERS OF THE BLADDER Clinical information about a functional disorder can be elicited by a detailed description of the symptoms observed, but insight into bladder function has only come from the introduction of urodynamic measurements.

4.1. Develomnt

of Human

Urodynamics

Human bladder pressure was probably first measured during attempts to estimate intra-abdominal pressure (Schatz, 1872). Measurement of bladder pressure, rectal, and intraperitoneal pressures showed that bladder pressure, however, could be independent of intra-abdominal pressure (Dubois, 1876). Voiding was shown to occur without a rise in abdominal pressure, implying that the bladder contracts actively (Moss0 and Pellacini, 1882). Simultaneous filling and pressure recordings (Genouville, 1894) showed a bladder pressure rise associated with the desire to void. Thus, over a century ago, urodynamics established important basic aspects of human bladder physiology. Modern electronics permitted the current urodynamic era, beginning with simultaneous recording of pressure and flow (von Garrelts, 1957); dynamic imaging, videourodynamics, was added (Caine and Edwards, 1958). Urodynamics became popular for diagnosis and, to a lesser extent, research. Standardisation of terms was achieved by the International Continence Society (Abrams et al., 1988). Debate, however, continues over the indications and appropriate techniques for urodynamics, as well as the interpretation of results. The techniques have been reviewed in detail (Abrams, 1983).

4.2.

Current Clinical

Urodynumic Techniques

During filling, bladder pressure is recorded via a urethral catheter; simultaneous rectal pressure recording allows electronic derivation of subtracted detrusor pressure. Filling rates (typically 20-50 mL/min) greatly exceed physiological filling rates. The patient is usually supine or sitting, and

may be imaged simultaneously. During voiding, detrusor pressure and urinary flow rate are generally both recorded. The cystometrogram is interpreted in terms of compliance, capacity, contractility and sensation (Abrams, 1983). Compliance during a volume change and maximum cystometric capacity are defined, respectively, as the change in bladder volume per unit pressure change, and the volume at which the patient can no longer delay voiding (Abrams et al., 1988). The assessment of contractility is difficult and controversial. Bladder sensation is usually assessed just by direct questioning. Urodynamic parameters vary with age and gender (Torrens, 1987a). Typical maximum cystometric capacities are 350750 mL in men and 250-550 mL in women. Only a small rise in pressure, typically less than 10 cm HzO, should occur during filling, producing the flat filling phase of the cystometrogram indicative of normal compliance. Voiding pressure, expressed as maximum detrusor pressure or detrusor pressure at peak flow (Pdet Qmax), increases with age in men and falls with age in women (Torrens, 1987a). The very few published pressure-flow data in normal subjects are generally unsubtracted. Typical unsubtracted bladder pressures at maximum flow are 40-65 cm Hz0 in women and 60-90 cm Hz0 in men (Torrens, 1987a). Measurement of resting bladder pressure and micturition pressure in women and men regarded as clinically or radiologically unobstructed showed median rises in bladder pressure during voiding of 23 cm Hz0 and 36 cm Hz0 for women and men, respectively (Smith, 1968), similar to detrusor pressure at peak flow in women (Torrens, 1987a) and men (Jensen et al., 1984).

4.3.

Problems with Clinical Urodynamics

Controversy about urodynamics is not new. Filling cystometry (Genouville, 1894; Schwarz, 1915) was criticised by Adler (1920), who advocated cystometry by incremental emptying, since he believed that the detrusor would react quite differently to rapid filling compared with slow gradual filling. Schwarz, however, subsequently found no difference between the two techniques (Schwarz, 1920). Two techniques that may make urodynamics more representative of normal bladder function are suprapubic catheterisation and ambulatory urodynamics. Suprapubic catheterisation avoids both anaesthesia for urethral catheterisation and subsequent stimulation due to a urethral catheter (Abrams et al., 1983a). It also avoids any catheter-related urethral obstruction, which may raise measured voiding pressure (Smith, 1968). However, the rise in voiding pressure with a fine urethral recording catheter is probably insignificant, and most urodynamic units use urethral catheters. Ambulatory urodynamics involves natural-filling, recording over several micturition cycles whilst permitting the subject to carry out activities resembling those of normal daily life. In normal men and women, lower end-filling pressures, higher voiding pressures, and lower voided volumes were found with ambulatory urodynamics than with conventional cystometry (Rob-

84

W. H. Turner and A. F. Brading

ertson et al., 1994). This was seen as evidence that ambulatory urodynamics inhibited detrusor function less than conventional urodynamics.

struction and in other patients with no evidence tion (Bates, 1971).

of obstruc-

5. THE UNSTABLE BLADDER 5.1. The Clinical Condition

5.1.2. Symptoms. The cardinal symptoms of the unstable bladder are urgency, urge incontinence, frequency, nocturia, and enuresis. However, instability is defined urody namically because symptoms do not predict instability reliably. Unstable contractions do not always cause urgency and urgency is not always caused by unstable contractions (Bates, 1971). Urgency occurred in 70% of patients with normal urodynamics and in 85% of those with instability, suggesting that it cannot be used to distinguish between the two groups (Abrams et al., 1983b). Furthermore, although 89% of patients with frequency, nocturia, and urge incontinence were unstable, the success of predicting instability from the symptoms and signs, even in an experienced unit, was only 3148% in women and 53% in men (Abrams et al., 1983b). This suggests that other than incontinence, the filling symptoms (Abrams, 1994) of unstable patients may not necessarily be caused by unstable contractions. This is important when considering the effects of treatment because abolishing unstable contractions may not resolve all filling symptoms and symptomatic improvement may not imply resolution of instability. Indeed, phasic contractions are found in asymptomatic subjects. Instability occurred in 25% of 13 asymptomatic middle-aged men (Jensen et al., 1984). Involuntary detrusor contractions were found with ambulatory urodynamics in 38-69% of healthy volunteers (van Waalwijk van Doorn and Zwiers, 1990; Robertson et al., 1994). Their high prevalence in asymptomatic subjects was seen as evidence that instability may be an unusual, al, though normal, variant rather than abnormal (TurnerWarwick, 1979).

5.1.1. History. The first unstable contractions probably were recorded in humans towards the end of the 19th century during the early recordings of human bladder pressures (Dubois, 1876; Genouville, 1894). Unstable contractions associated with bladder dysfunction were seen during World War I in soldiers suffering from spinal injuries or exposure to severe cold. These soldiers suffered from urge incontinence, and phasic pressure rises were seen using urodynamits (Schwarz, 1915). A gradual return of bladder contractions after spinal injury was believed to result from the emergence of a sacral spinal reflex, and it was proposed that phasic bladder pressure rises, in general, may be caused by reflex overactivity (Denny-Brown and Robertson, 1933b). The term “uninhibited neurogenic bladder,” denoting urgency, urge incontinence, or both, associated with phasic bladder contractions, became popular, particularly in the United States. It was believed to be due to overt neurological disease or, in those with no neurological findings, lack of normal cortical control over reflex bladder activity (Lapides, 1953). Those in the latter group were also described as having ‘dyssynergic detrusor dysfunction’ (Hodgkinson et al., 1963). Bates introduced the term ‘unstable bladder’ and recognised that apart from patients with neurological disease, instability also occurred in patients with outflow ob-

5.1.3. Occurrence. The unstable bladder occurs in patients with bladder outflow obstruction, those with a clear neurological lesion, and those with neither, so-called idiopathic instability. Idiopathic unstable bladder contractions and those associated with outflow obstruction are now defined as detrusor instability, whereas unstable contractions associated with neurological disease are defined as detrusor hyperreflexia (Abrams et al., 1988). Obstructive instability occurs in up to 60% of patients undergoing prostatectomy, and up to two-thirds of them become stable postoperatively (Abrams et al., 1979). lnstability is also associated with urethral stricture (Bates, 1978), colposuspension (Cardozo et al., 1979), and insertion of an artificial urinary sphincter (Bauer et al., 1986). Detrusor hyperreflexia is associated with lesions at each neural level involved in the control of bladder function. In patients with urinary symptoms and with either dementia, stroke, multiple sclerosis, or Parkinson’s disease, detrusor hyperreflexia was found in 62%, 95%, 67%, and 75%, respectively (Khan et al., 1981; Awad et al., 1984; Griffiths et al., 1990; Pavlakis et al., 1983). In spinal cord lesions, neurological and urological findings often correlate poorly (Wein, 1992); however, detrusor hyperreflexia occurs frequently. ldio-

4.4.

Classification of Bladder Disorders

Urodynamic investigations can identify bladder disorders and provide information that allows them to be classified. Many types of classification of voiding dysfunction, however, are possible, as expertly reviewed by Wein and Barrett (1988). For the purposes of this review, the most useful classification is a functional one, limited to the bladder itself, as we are not directly concerned with disorders of the outlet. Alterations in the smooth muscle can lead to failure of the bladder to store urine or to empty properly. Failure to store can be because of involuntary contractions of the bladder wall, decreased compliance or increased sensitivity of the micturition reflex. Failure to void can be because of reduced ability of the smooth muscle to contract, caused either by peripheral neuropathy or abnormalities of the smooth muscle. Although these failures in storage and voiding can be recognised, there are considerable difficulties inherent in investigating the actual changes underlying the disorders. Most progress has been made in conditions that can be mimicked in animals, and the two best studied disorders are those of involuntary contractions of the bladder wail (the unstable bladder) and diabetic neuropathy. In the next two sections these two conditions will be considered in more detail.

85

Bladder Smooth Muscle in Health and Disease pathic detrusor instability is diagnosed when outflow obstruction has been excluded in a unstable patient without overt neurological disease. Neurological lesions have been sought and never found in such patients (Del Carro et al., 1993).

5.2. Clinical Eoridence for the Aetiology of Detrusor Instability 5.2.1. Obstruction and age. The clinical association of instability with obstruction, and its frequent resolution after relief of obstruction, suggest strongly that obstruction causes instability. However, the observation that about 50% of men with or without obstruction were unstable (Abrams et al., 198313) suggested that age-related changes, rather than obstruction, may produce instability (Abrams, 1985). In men with lower urinary tract symptoms and prostatic enlargement, the degrees of instability and obstruction often are not correlated, and it has been suggested that obstruction and instability are independent of each other and are both consequences of ageing (Rosier et al., 1995). The fact that symptoms similar to those seen by elderly men with prostatic obstruction occur with equal frequency in elderly women (who are seldom obstructed) is consistent with an effect of age (Lepor and Machi, 1993). Furthermore, in a large series of women with urodynamically proven bladder outflow obstruction, although 40% were unstable, none of the subset who had urodynamics reverted back to stability after relief of obstruction (Farrar et al., 1975). The degree of obstruction was less than that generally seen in men, so the lack of reversion should not be overemphasised; however, it suggests that the relationship between obstruction and instability is not entirely clear-cut. In men with benign prostatic enlargement, as age increases, detrusor instability becomes more common and both flow rate and voided volume decrease (Simonsen et al., 1987). The decrease in flow rate could represent increasing obstruction with age, explaining the increased instability. However, in the absence of pressure-flow data, an alternative explanation is that an age-related increase in instability reduced functional bladder capacity and hence flow rate, with no increase in obstruction (Abrams et al., 1983a). Indeed, of 12 unstable elderly patients, only 1 became stable after prostatectomy (Gormley et al., 1993), suggesting a higher rate of idiopathic instability than in younger men. Age-related changes, however, cannot account either for the resolution of instability after relief of obstruction, or for cases of instability associated with outflow obstruction due to strictures, stress incontinence surgery, or artificial sphincter surgery; this suggests that age notwithstanding, obstruction indeed can result in instability. 5.2.2. Neurological factors. The occurrence of hyperreflexia in diverse neurological diseases implicates the nervous system in its aetiology. Altering neurotransmission at various levels may influence instability, supporting a neurogenie component. Hyperreflexia induced by ice water can

be abolished by intravesical bupivicaine, suggesting that bladder afferents participate in its aetiology (McInerney et al., 1992). This is supported by the disappearance of hyperreflexia after intravesical capsaicin, which activates C fibre afferents and damages them after longer exposure (Fowler et al., 1994). Although in some studies phasic contractions could not be abolished with epidural or spinal blockade (Plum, 1960; Schwarz, 1920), in others, instability has been reduced or abolished by spinal and epidural anaesthesia (Nesbit and Lapides, 1948; Hodgkinson et al., 1963), cauda1 anaesthesia (Bates, 197 1), and sacral root block (Torrens, 1974). A cortical defect that prevents normal inhibition of inherent rhythmic contractions was suggested as a cause of instability (Lapides and Costello, 1969), and this is supported by the observation that detrusor hyperreflexia does occur in some patients with frontal lobe lesions (Andrew and Nathan, 1964).

5.2.3. Urinary tract infection. Urinary tract infection (UTI) often produces urgency and may worsen the symptoms of instability. In one study, instability was converted to stability following treatment of UT1 in five of eight unstable patients (Bhatia and Bergman, 1986), thus supporting a role for UT1 in the aetiology of instability. However, in another study, no instability occurred in the early recovery phase after spinal injury, despite very frequent infection due to catheterisation (Holmes, 1933). In a study on men with prostatic obstruction, the incidence of instability was the same in those with and without UT1 (Andersen, 1976), and in over 2000 patients, only 3 of 35 with UT1 at the time of urodynamics were unstable (Bates, 1978). Evidence that infection causes detrusor instability, therefore, is lacking.

5.2.4. Low compliance. Cystometry may show steadily rising detrusor pressure during filling. This is low compliance; its importance is its association with upper tract damage (Styles et al., 1986; Hackler et al., 1989). Although physical changes, shown to occur in the hypocompliant detrusor (McGuire, 1984), were thought to cause low compliance, ambulatory monitoring showed clearly that patients with low compliance on conventional studies were unstable on ambulatory studies, implying that low compliance is an artefact of fast-fill cystometry (Styles et al., 1988; Webb et al., 1992). There is considerable evidence that the two clinical associations with instability, obstruction, and neurological lesions, in different situations, may be causal relationships. However, to define the pathophysiology further, and study its aetiology, requires techniques that cannot be justified in humans, and necessitates the development of animal models.

5.3. Eeerimental

Induction

of Bladder

Instability

Animal studies are useful for two reasons: firstly, to determine whether symptoms resembling human bladder instability can be induced in animals through procedures that

86

mimic the conditions known to be associated with instability in humans, and secondly, to study the properties of smooth muscles from unstable bladders of similar aetiology with smooth muscle from normal age-matched controlssomething that cannot easily be achieved with human tissue. Although the strict clinical definition of instability (Abrams et al., 1988) cannot be applied literally to animals, as it is not possible to determine whether or not a rise in bladder pressure is uninhibitable, urodynamic recordings from experimental animals in some models can demonstrate changes that resemble urodynamic findings in humans with unstable bladders sufficiently closely to justify the assumption that instability has been induced. Models of obstructive instability. The experimental creation of an outflow obstruction is an obvious and relatively easy intervention that can be performed on animals. The obstruction can be complete or partial, immediate or gradual in onset. There were a few early studies of experimental acute obstruction dating from the end of the 19th and first half of the 20th centuries in which overdistension and damage to the bladder occurred in dogs or rabbits (Guyon and Albarran, 1890; Shigamatsu, 1928; Creevy, 1934) and two studies of chronic obstruction in the dog (Creevy, 1934; Duncan and Goodwin, 1949), neither producing very useful results. Partial obstruction of the rabbit urethra was further investigated in several studies in the 1960s and 1970s (Arbuckle and Paquin, 1963; Brent and Stephens, 1975; Mayo, 1978), and then extensively from 1983 onwards by Levin’s group in Philadelphia and by Harrison and colleagues (1990), but urodynamic evidence of functional symptoms resembling instability in the human were not recorded in this model. Models of obstructive instability, however, have been described in the pig, the rat, and the guinea-pig. The first clear evidence of a partial obstruction leading to instability in an animal model was presented by Jorgensen et al. (1983) in the pig, and the model was further developed by Sibley (Sibley et al., 1984; Sibley, 1985, 1987), Speakman (1987), and Turner (1997). Detrusor instability was seen in 6 of 7 obstructed pigs under anaesthesia (Jorgensen et al., 1983). During conscious urodynamics, instability (defined as phasic contractions over 15 cm HlO) occurred in 9 of 14 obstructed pigs, and 2 more had low compliance (Sibley, 1985). During conscious urodynamics, Speakman found that 71% of 14 pigs and 87% of 8 mini-pigs were unstable (Speakman et al., 1987), and 4 of 5 obstructed animals were unstable during conscious urodynamics with ketamine sedation (Guan et al., 1995). Oufflow obstruction produced in the rat by urethral ligation (Malmgren et al., 1987) or by testosterone-induced prostatic enlargement (Maggi et al., 198913) led to instability during conscious urodynamics in 83% and 61% of rats, respectively. This has proved a useful small animal model of instability. In the guinea-pig (Mostwin et al., 1991; Williams et al., 1993) and rabbit (Harrison et al., 1990), there is 5.3.1.

W. H. Turner and A. F. Brading less clear evidence that outflow obstruction results in bladder instability, although these animals have been useful in looking at the other effects of outflow obstruction. In guinea-pigs, Mostwin and colleagues (1991) found outflow obstruction to result in various urodynamic patterns under anaesthesia, including one resembling instability. In the subsequent study (Williams et al., 1993), however, the development of phasic activity during filling was inconsistent and justifiably could not be called instability.

5.3.2. Models of nonobstructive instability. A condition similar to multiple sclerosis with low compliance during cystometry has been produced in the rabbit using inoculation with guinea-pig spinal cord (Hassouna et al., 1983). Also, in the rabbit, an acute model described as hyperreflexia has been produced by penis ligation under ketamine and xylazine anaesthesia, resulting in phasic bladder contractions not seen without ligation (Levin et al., 1992), although clearly, this is not hyperreflexia, as defined clinically (Abrams et al., 1988). Similar hyperreflexic contractions can be seen in the rat with acute obstruction. In the pig, instability was produced by two paradigms designed to denervate the bladder: transection and prolonged elevation of intravesical pressure (Sethia et al., 1990). Transection, however, did not result in measurable denervation of the detrusor, presumably because ganglia were present in the bladder wall, and the transection thus produced decentralisation rather than denervation. Bladder transection in the dog also produced decentralisation, with preservation of intramural ganglia (Staskin et al., 1981). A model of “neurogenie bladder function disturbance” has been created by subarachnoid alcohol injection in the mini-pig, but no urodynamic details were given (Mau et al., 1980). 6. DIABETIC NEUROPATHY 6.1. The Clinical Condition When the high prevalence of diabetes mellitus is considered, together with the apparently high frequency with which it involves the bladder, the literature on the clinical effects of diabetes on the lower urinary tract is sparse, particularly compared with that on the effects on the bladder of experimental diabetes. The effects of diabetes on the bladder have been reviewed in 1978 (Frimodt-Meller, 1978) and more recently (Nickel1 and Boone, 1996). The traditional view of diabetic bladder dysfunction holds that there is delayed first sensation during filling and increased bladder capacity, interpreted as sensory impairment (Nickell and Boone, 1996). The prevalence of these features has been supported by a recent study of apparently unselected and asymptomatic diabetic patients (Ueda et al., 1997). This urodynamic situation then progresses, with the development of poor contractility, and leads to impaired bladder emptying and residual urine. However, classical so-called diabetic cystopathy may only occur in a minority of symptomatic diabetic patients, and symptoms may also be due ei-

87

Bladder Smooth Muscle in Health and Disease ther to bladder outflow obstruction et al.,

1995).

Importantly,

or to instability

it seems that patients

(Kaplan

7. FACTORS

with re-

SMOOTH

RESULTING

MUSCLE

OF

cently diagnosed diabetes and with no urinary complaints

7.1.

may have evidence of established diabetic bladder dysfunction. It seems fair to say that we remain unsure as to what

In obstructed bladders, and those from animals with diabe-

degree dysfunction

able hypertrophy of the smooth muscle cells. In both condi-

of motor nerves, sensory nerves, and the

detrusor itself contribute

to the bladder dysfunction

in dia-

betes, although skin sensation testing has indicated that evidence of autonomic

neuropathy

ated with bladder dysfunction uncertainty

is common

and is associ-

et al.,

(Ueda

is at least partly because clinical

the sensory and motor

innervation

1997).

This

assessment of

of the lower urinary

tract is crude, and although several clinical neurophysiolog ical tests have been used in this context, (Del Carro et al., 1993; Delodovici clinical relevance

none seems ideal

and Fowler, 1995). The

of this is that we are unlikely to improve

the management

of diabetic patients with lower urinary tract

dysfunction without a clear understanding

of the pathophys-

iology of their problem. 6.2.

Hypertrophy

IN ALTERATIONS

FUNCTION

and Diuresis

tes mellitus, the bladders are enlarged and there is considertions, changes

in the physiological

properties of the cells

can also be found. An obvious question that arises over interpretation

of the data is: are these two outcomes linked? It

is intuitively

likely that hypertrophy

is a result of an in-

creased work load on the bladder wall, since this will occur both in obstruction

(where higher pressures have to be gen-

erated to overcome

the outflow resistance)

and in diabetes

(where there will be an increased frequency of micturition). Do the cellular changes resulting in hypertrophy necessarily lead to the observed alterations Is there There

any link between

in physiological

hypertrophy

properties?

and neuropathy?

are several useful models that help to resolve these

issues, such as models where the bladders become unstable without hypertrophy [the transected and distended bladders

Experimental

Induction of Diabetic

Neuropathy

of Sethia

(Sethia,

1988; Sethia et al., 1990)] and models in

Diabetes mellitus can be induced in rats and rabbits by ad-

which there is hypertrophy caused by diuresis without neur-

ministration

opathy or instability.

of streptozotocin

(STZ)

or alloxan.

also a strain of rats (BB) that spontaneously tes mellitus treatment p-cells

at the age of 60-90 to survive. STZ

in the pancreatic

There

is

develops diabe-

days and needs insulin

and alloxan

both damage the

islets, and depending

on the de-

gree of damage, prevent or reduce the production of insulin, resulting These B-cells

in high circulating

toxins are thought through

glucose levels and diabetes.

to produce their effects on the

free radical generation,

the B-cells

being

1988; Sethia et al., 1990) that the physiological

changes in the bladder smooth muscle that lead to instability can occur without hypertrophy, experiments,

that hypertrophy

pathophysiological

rats develop an increase in plasma glucose

and from the diuresis

does not necessarily

The most studied diuretic models are rats with hereditary diabetes insipidus [Brattleboro Eika et al., 1994a,b)],

rats (Malmgren

et al., 1992;

or animals made diuretic with fruseor by adding 5% sucrose to the

drinking water. This latter procedure does not increase the

levels and diuresis, with an increase in both the volume and

blood glucose levels (Santicioli

frequency

1995) and seems not to result in any neuropathy,

of micturition

Eika et al., 1994a).

(Andersson,

P. 0.

et al.,

The animals grow less well than con-

trols, but the bladders get larger and more compliant coln et al., 1984b; Santicioli et al.,

1988; Malmgren

Eika et al., 1994a), old. Other

et al., 1987; Andersson,

et al.,

198913; Steers et al.,

a small increase in micturition

flexes, but not in latency, ganglionic tion velocities,

in central reconduc-

BB rats lose weight after the onset of diabetes, micturition frequency and volume both increase, and the bladders increase in weight, capacity and compliance. The changes comparison

the compliance for micturition

to,

those

caused

by STZ-induced

leading to an increased volume threshold

of the BB rats.

volumes and bladder ca-

pacity), but little change in the contractile

properties of the

smooth muscle cells. The increased compliance may be caused by a reduction in the amount of collagen wall (Eika et al., 1994a).

in the bladder

Although in the case of diuresis, it is thus clear that a factor that leads to hypertrophy also leads to associated changes in i.e., increased

compliance

and de-

creased collagen; in the case of obstruction, the hypertrophic bladders are, in contrast, hypocompliant and with increased collagen. Thus, it seems that hypertrophy can result

modest in

independently from other changes in the bladder wall. Many

diabetes’

of the effects of STZ on bladder function, however, are likely

(Longhurst, 1991; Longhurst and Levin, 1991), the quantitative difference possibly due to the ameliorative effect of the insulin treatment

that the response to diuresis, how-

(larger micturition

bladder wall function,

(1990).

similar to, but quantitatively

fre-

hypertrophy of the smooth muscle cells) and an increase in

or thresholds of nerve fibres, by Steers et al.

are ‘qualitatively

but does

in voiding

ever caused, is an increase in the bladder weight (with some

of the STZ.

transmission,

an increase

I? 0.

pressure by Anders-

and small differences

causing

1990;

in residual volume was seen by Steers et al.

son, P. 0. et al. (1988),

drinking,

quency. It is interesting

changes have been seen variably, and may de-

An increase

stimulate

et al., 1987; Tammela et al.,

(Lin-

leading to an increased volume thresh-

pend on the length of time after administration (1990),

1988;

lead to

changes.

mide (Levin et al., 1995),

unusually susceptible to such damage. STZ-diabetic

al. (Sethia,

It is clear from the work of Sethia et

to be the result of diuresis [see e.g., Kudlacz et al. (1989a)], although, particularly later in the disease, additional effects occur that could be due to neuropathic changes.

W. H. Turner and A. F. Brading

88

7.2.

Alterations

in Neuronal lnput

Many of the voiding dysfunctions tion in the neuronal

control

with spinal injuries

responses of the bladder or bladder strips to capsaicin,

are caused by malfunc-

of micturition,

and spina bifida, and probably

neuronal diseases and diabetic neuropathy. ations in the innervation

with

However, alter-

of the detrusor, whether

actual structural changes in innervation pattern of activation only in functional

as is obvious

due to

or changes

in the

of the motor neurones, can result not

disorders, but also in secondary changes

in smooth muscle physiology that contribute toms of the disease. It is common

to the symp-

for adaptive changes to

occur in end organs in response to changes in their innervation, as seen, for instance,

in the supersensitivity

curs in smooth muscles in response to denervation

that oc(Westfall,

1981). The increased work load, resulting in the hypertrophy described

in Section

change (increase)

7.1, will again be mediated by a

in activity in the motor nerves, although

the outcome will be affected by other factors, such as the elevated intravesical turition

pressure occurring with obstructed

mic-

and the increased rate of filling and frequency

of

emptying seen with diuresis. 7.2.1.

Diabetic

neuropathy, treatment,

neuropathy.

With

reference

to diabetic

leading to diabetes, does induce neuropathic

ef-

fects in rats, which may make this a realistic model for huThese

effects

may well be responsible

for

some of the changes in the properties of the smooth muscle. A reduced conduction in human 1986).

diabetics

Impairment

velocity of peripheral nerves is seen and in animal

of sympathetic

haviour in STZ-treated

models control

(see Greene, of bladder be-

rats, as opposed to sucrose-fed and

control

animals, has been demonstrated

(1988).

Steers and colleagues

in conduction

velocity

(1990)

by Kudlacz et al.

found no differences

in the postganglionic

motor neu-

rones, but showed that there are some differences working of the micturition

in the

reflex in treated animals-none

of them showed any evidence of a spinal micturition

reflex,

although 38% of the controls did; also, there was no facilitation of the supraspinal reflex by stretch in any of the diabetic rats, although this occurred in the controls. Later, Steers

and colleagues

(1994)

showed that neuronal

bodies in the pelvic ganglia that innervated were swollen in STZ-treated of afferent neurones

cell

the bladder

animals, and that the number

projecting

to the dorsal root ganglia

was decreased, and the sizes of the neurones smaller than in the controls.

Nadelhaft

and colleagues

swelling of the postganglionic bladder in STZ-diabetic

neurones

(1993)

also found

projecting

to the

rats, but they found similar swell-

ing in rats with sucrose-induced this is a use-dependent

diuresis, suggesting that

effect rather than an STZ pathol-

ogy. In fact, the consensus of opinion is that there probably are no functional changes in the motor arm of the micturition reflex in STZ- or spontaneously diabetic rats over the time periods studied. However, further evidence for impairment of sensory innervation

an

such as substance

P from nerve terminals, and can result in contraction

of the

smooth muscle. Several authors have found diminished

re-

sponses of bladder strips or isolated bladders to capsaicin in STZ-treated

animals

(Dahlstrand

et al.,

1992; Kamata et

al., 1993; Pinna et al., 1994), and others have found an increase

in the bladder

(Santicioli

content

of sensory neuropeptides

et al., 1987; Andersson

some impairment

et al., 1992), suggesting

of sensory neuronal

ability to release transmitters.

function

and their

Some papers, however, report

no change in capsaicin and substance P sensitivity (Santicioli et al., 1987; Kudlacz et al., 198913). Problems with neuronal release of transmitters

have also been suggested by

Tong et al. (1996) from studies on synaptosomal preparations from rat bladders 2 weeks after induction They concluded

lease from both sympathetic Other

evidence

of STZ diabetes.

that there may be impaired transmitter and parasympathetic

for nerve terminal

creases in noradrenaline

re-

nerves.

damage, including

de-

uptake, and in choline acetyltrans-

ferase activity were found in STZ-fed,

but not sucrose-fed,

rats (Kudlacz et al., 1989a).

there is evidence from several groups that STZ

man diabetes.

agent that releases sensory neuropeptides

has come from studies on the

7.2.2.

Partial denervation.

Partial denervation

trusor, in fact, is commonly dysfunction,

of the de-

seen in bladders with voiding

and is probably responsible both for decreased

nerve-evoked

contractility

and for the physiological changes

such as increased excitability bility (Brading and Turner, tial denervation badawi et al.,

contributing 1994).

is seen in ageing (Gilpin

1993a),

to bladder insta-

In human bladder, par, et al., 1986; El-

but a more marked denervation

has

been described in unstable bladders associated with outflow obstruction

(Gosling

neuropathy

(spina bifida, German et al., 1995), and in peo-

ple with idiopathic instability Section

et al.,

instability.*

and denervation,

et al.,

This association 1984a)

model of instability

between and then

(Speakman,

and has also been seen in obstructed

(Williams

1987),

as described in more detail in

7.3, was first suspected (Sibley,

seen in the pig obstructive 1988),

1986; Harrison

guinea-pigs

et al., 1993) and rabbits (Harrison et al., 1990).

Distension

of the bladder to induce denervation

can also

result in instability (Sethia et al., 1990). Bladder instability

is also seen in conditions

there is no obvious actual denervation

in which there may be reduced activation cells through their preganglionic citatory

input, however

of the ganglion

input. Lack of normal ex-

achieved,

will result in adaptive

changes in the smooth muscle. The experimental tion of the bladder in pigs (Sethia et al., activation

transec-

1990), preventing

of the bladder wall ganglia through

roots, results in bladder instability, denervation

in which

of the detrusor, but

although

the sacral

no structural

of the detrusor can be seen.

*Mills, 1. W., Greenland, J. E., McMurray, G., Ho, K. M. T., Noble, 1. G. and Brading, A. F. (1997) Detrusor denervation in idiopathic instability. In: Neurourology Urodynamics ICS Japan 1997 Meeting.

89

Bladder Smooth Muscle in Health and Disease

7.3. The Link Between Obstruction and Denermtion At first sight, there is nothing obviously linking outflow obstruction and denervation, but a reasonable scenario is unfolding (Brading, 1997) that incorporates hypertrophy and may lead to instability. If one considers the immediate effects of a sudden urethral obstruction during micturition, the first thing that will happen is that the intravesical pressure will rise, and this will result in a change in the pattern of sensory nerve activity-the activity of any pressure-sensitive nerves will increase and the activity of stretch-sensitive nerves will not decline as rapidly as during normal micturition, due to the slower rate of emptying of the bladder. The whole micturition reflex will be prolonged because of the increased sensory nerve activity, and emptying will require an increased energy utilisation. If the increase in outlet resistance persists, these consequences will occur every time micturition is initiated. This may trigger adaptations designed to increase the effectiveness of emptying, and in these early stages when there will be increased excitatory input to the detrusor, the smooth muscle excitability may be reduced. Hypertrophy of the bladder wall and increased collagen deposition will occur-this is a universal response to partial obstruction in all animals and humans; it is not known exactly how it is triggered, but there is evidence from studies in the rabbit (Buttyan et al., 1992; Santarosa et al., 1994) that short-term partial obstruction can increase the expression of basic fibroblast growth factor and inhibit the expression of transforming growth factor-pl. These changes reverse on release of obstruction. There is also an increased expression of the proto-oncogenes c-myc, N-ras, and Haras, and a similar increase in c-myc and c-fos in the guineapig (Karim et al., 1992). Another consequence of the raised intravesical pressure during voiding will be a reduction in blood flow to the bladder wall. The combination of hypertrophy of the wall with the increased energy expenditure and reduced blood flow may lead to metabolic substrate deficiency and ischaemic damage. Prolonged high pressure micturition contractions associated with reduced blood flow and extended reduction in oxygen tension in the bladder wall have been shown directly in the obstructed pig model (Greenland, in Brading, 1997). Anoxia and substrate depletion can reduce the ability of the isolated rabbit bladder to empty in response to nerve- or agonist-mediated stimulation (for a review, see Levin et al., 199413). In the long term, metabolic depletion may also damage the nerves. Experiments on isolated strips of guineapig detrusor (Pessina et al., 1997) have shown that simultaneous removal of glucose and oxygen causes a rapid abolition of the contractile response to all excitatory stimuli. After a 1-hr deprivation, although the ability of the tissue to respond to agonists recovered nearly fully on readmission of oxygen and glucose, the response to intrinsic nerve stimulation was permanently reduced, and a 2-hr deprivation produced permanent loss of nerve-mediated responses in

many strips, although a slow recovery in the contraction to applied agonists still occurred. These tissue strips probably contained only nerve endings, and it is possible that the nerve cells themselves are even more susceptible to the deprivation of oxygen and substrate, which would occur in ischaemia. One thus could postulate that obstruction may lead to an initial increase in activity of motor neurones, followed by a subsequent decrease due to damage of intrinsic neurones. This neuronal damage may lead to partial denervation, reduced excitatory input, and altered physiological properties of the smooth muscle. In the following section, we will discuss the changes seen in unstable bladders and also the changes produced in smooth muscle cells in response to an outflow obstruction. Many experimental studies have been carried out in animals in which urodynamic assessment either was not carried out or did not show behaviour resembling bladder instability, but we will also discuss those changes that might result in bladder instability where it does occur.

8. SMOOTH MUSCLE IN BLADDERS IN THE DISEASED STATE 8.1. Obstructed Bladders 8.1.1. Early observations. The association between hypertrophy of the bladder wall and outflow obstruction has been long established. The first study of changes in the physiological properties of detrusor smooth muscle associated with both outflow obstruction and bladder instability was carried out by Sibley (1984a) in pig and human specimens. The study was instituted in the belief, then current, that all unstable bladders in fact were hyperreflexic (i.e., with increased activity in the micturition reflex arc) and that the abnormality would reside in either the sensory pathways or the central control of the micturition reflex. Had this been the case, then the motor innervation should have been normal, and the smooth muscle responsiveness to agonists, if anything, suppressed due to down-regulation of receptors as a consequence of the hyperreflexia. Jargensen’s technique for producing pigs with unstable bladders was adapted (JBrgensen et al., 1983), and the properties of isolated strips of pig detrusor from normal and unstable bladders were studied and compared. Similar studies were undertaken on strips obtained at open prostatectomy from patients with demonstrably unstable bladders, and on strips from the normal bladders of cadaver organ donors and from cystectomy specimens. The results were unequivocal. In both species, the strips from unstable bladders were less responsive to activation of their intrinsic nerves, but showed supersensitivity to muscarinic agonists, high potassium solutions, and direct activation with electrical depolarisation. These unexpected results led to the prediction that the unstable bladders might be partially denervated (see Section 7.2.2), a prediction that subsequently proved correct (Speakman et al., 1987).

W. H. Turner and A. F. Brading

90 8.1.2.

Variability

look at functional

simple to

Assessment of the contractility

of the smooth muscle and

changes in the properties of smooth mus-

of the results.

It is relatively

how it changes after obstruction

is difficult. From a func-

cle strips dissected from bladders of humans and animals

tional point of view, it is the ability of the whole bladder to

that have an outflow obstruction.

generate and sustain an increased intravesical

nificant

differences

There are, however, sig-

in the functional

effects of obstruction

to empty that is important,

between species, and these depend also on the severity and

fraught with difficulties (Griffiths,

duration of the obstruction.

volvement

the changes

in human detrusor, and this indeed has been

attempted;

however, the results are complicated

the patient-to-patient and severity quences.

Ideally, one would like to study

variation

of obstruction,

in age, sex, the duration

and the urodynamic

In animals, a more consistent

investigated,

because of

population

but again, there are considerable

between studies concerning

1991) because of the in-

of the outflow resistance and the problems of as-

sessing this. In vitro, studies on the whole bladder in which the outflow resistance can be controlled

might appear to be

more useful, but the difficulty of ensuring adequate supply

conse-

of oxygen and substrates to the muscle, particularly

can be

the bladder wall has thickened

variations

the severity and duration of ob-

comparisons

less reliable. In strips of muscle, the force pro-

critically on the amount and composition lar matrix. Since the results are commonly

variation

in the effects can be found, and the urodynamic

consequences The

of obstruction

physiological

also vary between species.

consequences

of obstruction

mans are more likely to be important gressive and partial obstruction obstruction

(since

are medical emergencies),

in hu-

in response to proacute or complete and so, we will dis-

with respect

to the weight

muscle, although

they may be a useful indication

tractile

animal bladders, the contractility

response

to intrinsic

The most beneficial

change in the physiological

properties of the smooth mus-

nerve stimulation

in the contractility

stimulation

the conis dimin-

response to applied ago-

in the ratio of the response

to nerve

and applied agonists between strips from nor-

mal and obstructed bladders is a valid observation.

The re-

would be an increase

sults from several different species and degrees of obstruc-

of the muscle to produce more rapid and

tion have been summarised by Levin and colleagues (1993).

cle in response to outflow obstruction complete

functional

of the

of the smooth

and commonly,

ished further than the contractile nists. This change studies.

the

of the smooth

properties of the bladder wall. In the majority of studies on muscle appears to be diminished,

Contractile

some

sectional area) rather than the smooth muscle content, results say little about the actual contractility

obstructed

8.1.3.

only normalised

workers make the effort to normalise with respect to cross

subsequent

with a mild or progressive obstruction.

of the extracellu-

of the strip (although

cuss the changes seen in humans with outflow obstruction to benign prostatic hyperplasia and in animals

makes

duced will depend not only on the size of the strip, but also

struction imposed. Even with carefully designed procedures inter-animal

when

after obstruction,

for creating uniform obstruction,

considerable

pressure and

but assessing this in viva is

emptying against the increased resistance.

is indeed some evidence

There

from animal studies that the con-

Where

the sensitivity

of the smooth muscle to agonists

has been studied, in some species, even if the size of the con-

tractility of the bladder wall may increase if the obstruction

tractile

is mild and does not lead to excessive hypertrophy

smooth muscle shows a supersensitivity. To assess changes in

(Kato et

response to agonist application

is diminished,

al., 1990, rabbit; Saito et al., 1993, rat). In the rat, the mild

sensitivity to an agonist when the contractile

obstruction

strips may be different

caused a less than

doubling

of the bladder

requires

the

ability of the

the full concentration-

weight, and the normalised force developed by muscle strips

response curves to be constructed,

in response to stimulation

response. The two curves then can be scaled to their own

cation

of the intrinsic nerves and appli-

of agonists increased

the rabbit,

in the obstructed

bladder. In

a whole bladder model was used, and in ob-

structed bladders that had only a mild hypertrophy, travesical

pressure

nerve stimulation

rise at constant

volume

the in-

to intrinsic

or applied agonist was larger than the

control, although with bladders showing a greater hypertrophy, the contractile response was diminished. Changes in the contractile proteins have also been found associated with hypertrophy in animals and in humans. There is an in-

maxima to compare sensitivity.

up to a clear maximum

Errors can easily be intro-

duced if the highest agonist concentration duce the maximal

response.

used does not in-

Nonspecific

supersensitivity

has been demonstrated clearly in strips from obstructed humans (Sibley,

1984a; Harrison et al.,

1987),

pigs (Sibley,

1987;

Speakman et al., 1987), and in rabbits (Harrison et al., 1990). Supersensitivity

is not seen in obstructed

rat, although

a

transient supersensitivity to agonists was seen in rat bladders after relief of the obstruction (Malmgren et al., 1990b)

crease in the intermediate filament and cytoskeletal proteins, an increase in the total contractile protein, an in-

or in obstructed guinea-pig bladders (Williams et al., 1993).

crease in the actin/myosin ratio, a change in the ratio of the

structed bladder smooth muscle in some species is an increase in the spontaneous activity. Spontaneous activity

myosin heavy chain isoforms, due to a decrease in SM2 and an increase in SMl, and an alteration in the actin isoforms

Another

change

in the contractile

behaviour

of ob-

(Malmqvist et al., 1991a,b; Samuel et al., 1992; Chiavegato et al., 1993; Kim et al., 1994; Berggren et al., 1996). How

can be very variable in strip preparations. It often takes 1 or 2 hr after a strip is set up for it to develop activity, and it is often suppressed when the strip is stimulated. Probably for

these changes affect contractile function is not known, but the changes can be rapid and are reversible.

this reason, few studies on detrusor mention spontaneous activity. The increase is very marked in the obstructed

91

Bladder Smooth Muscle in Health and Disease mini-pig,

where the spontaneous

smooth muscle also changes fused tetanic

contractions

activity

pattern

seen in strips of

and shows extensive

(Turner,

1997).

Such contrac-

Williams

and colleagues

(1993)

found clear evidence

partial denervation,

but no evidence

Electrophysiological

responses, however,

for

for supersensitivity. were not carried

agonists, whereas in the normal animals, the amplitude of

out. In the obstructed pig, the alterations in the smooth muscle behaviour are exactly as would be predicted by a de-

spontaneous

crease in the activity of the intrinsic nerves. The muscle is

tions can be as large as the maximal contractile contractions

is normally

response to

on a few percent

of

the maximum force a strip can achieve. An increase in the

more excitable,

incidence

cell to cell, and the muscle cells become supersensitive

of spontaneous

strips of obstructed

activity

human

has also been seen in

bladder

(Sibley

et al.,

applied agonists (Sibley,

1984).

This type of behaviour is very typical of well-coupled,

electrical

spon-

1987). Histological

activity spreads more easily from to

1987; Speakman et al., 1987; Fujii,

studies clearly demonstrate

denervation

have proposed that this may reflect an increase in the cell-

model, the smooth muscle physiology probably is changed

to-cell coupling (Brading and Turner,

has occurred (Speakman

that partial

taneously active smooth muscles such as in the gut, and we

by the longer-term

1994).

consequences

et al., 1987).

In this

of damaged intramural

nerves. 8.1.4.

Electrical

struction

properties.

The

on the electrical

clearly of considerable physiological

effects

properties

importance.

of outflow

ob-

of the detrusor are

Unfortunately,

The other approach that has been developed for studying the electrophysiological

properties of detrusor is to use iso-

lated cells and patch electrodes.

electro-

studies on normal detrusor have proved very

difficult to obtain, and it is really only in the guinea-pig and

berg and colleagues

rabbit that significant

berg, 1985; Ganitkevich

studies have been published (see, for

example, Creed, 1971; Callahan al.,

1983,

1991; Mostwin,

Mostwin,

and Creed, 1981; Creed et

1986; Fujii,

1988; Brading and

A great deal of work has

been carried out on guinea-pig bladder myocytes by Isen-

techniques

(see, for example,

Klockner

and Isenberg,

have been perfected

1991),

and Isenand similar

by Fry and colleagues

human bladder myocytes (Montgomery

for

and Fry, 1992; Gal-

1989; Bramich

and Brading, 1996). There are no

legos and Fry, 1994; Fry et al., 1994).

These methods will

published microelectrode

records from smooth muscle strips

allow detailed studies of the channels

and channel

proper-

in any large mammals or humans. It was because the guinea-

ties in the cell membranes

pig was a good animal for electrophysiological

structed bladders. No patch clamp work has been carried

an obstructed Williams

model was created

et al.,

1993).

The

seen were a decrease

et al., 1991;

electrophysiological

caused by outflow obstruction in this model (Seki et al.,

studies that

(Mostwin

changes

have been carefully studied

1992a,b,c).

in spontaneous

The main changes electrical

decrease in the time and space constants

activity,

a

of the membrane,

and changes that occur in ob-

out as yet on myocytes from obstructed humans

with benign

prostatic

that there was an increase in the activity of

(the cells from the obstructed also found small changes

but the action potential

duration was

(Gallegos

and

inward Cal+ current, although a small decrease in the den-

pump. No change

potential,

hyperplasia

sity of the inward Ca*+ current per unit cell area was seen

and evidence membrane

Some

Fry, 1994). These authors found no net change in the total

the Na+-K+

was seen in the resting

guinea-pigs.

studies, however, have been carried out on myocytes from

bladders were larger). They

in the channel

suggested that the action potentials

kinetics,

which

would have slowed ris-

prolonged, with a decrease in the maximum velocity of de-

ing and falling times similar to those seen in the guinea-pig

polarisation

(Seki et al., 1992~).

and repolarisation.

The conclusion

from these

studies is that in the guinea-pig with this degree of obstruction, there is a decrease in the electrical the cells.

It is interesting

smooth muscle function in response to denervation persensitivity

that

the changes

noted by Westfall

in

and colleagues

duced Na pump activity

coupling between cells, and re(Westfall

et al., 1975; Lee et al.,

which suggests that the responses in the obstructed

guinea-pig

could be the result of increased

postjunctional

It is unfortunate

activity in the

neurones.

on isolated cells

cannot

contribute

to knowledge

about cell coupling

or

changes in innervation. 8.1.5.

Studies

nerve activity will be the dominant

calcium

Contraction

stores and intrais initiated

rise in [Ca*+li, and, as described in Section

by a

2.4, this can be

achieved in the bladder by Ca*+ entry and by Ca*+ release from internal stores. Fluorescence

techniques

are available

cause of the changes

coplasmic reticulum can show changes in release properties. Recent studies, therefore, have begun to focus on the effects of obstruction on these processes. Cal+ release from

seen, rather than decreased activity following denervation.

intracellular

Indeed, the authors interpret their evidence

pathway

of choline acetyltransferase

showing an intact innervation

on intracellular

cellular free calcium ions.

for following changes in [Ca*+&, and studies on isolated sar-

It thus seems likely that in guinea-pigs with this particular obstruction regimen, the short-term increase in intrinsic

der content

that the experiments

can only shed light on changes in membrane properties and

are exactly opposite to this [su-

to agonists, decrease in the threshold for acti-

vation increased electrical 1975)],

to note

coupling between

(Mostwin

that the blad-

was not changed as et al., 1991). The

sensitivity to agonists, however, was not assessed. After a longer period of obstruction in a similar guinea-pig model,

stores can be mediated either through the IP,

(activated

Ca-induced characterised

Cal+

through release

by their

muscarinic

through

ability

receptors)

channels

or by

that can be

to bind ryanodine.

In ob-

structed rabbit bladder, a large increase in the number of ryanodine binding sites has been noted (Levin et al., 1994a),

92

W. H. Turner and A. F. Brading

indicating that each cell has an increased number of binding sites. This suggests that there is an increase in the surd face area of sarcoplasmic reticulum in these hypertrophic cells. The contractile response of the bladder to field stimulation also became much more sensitive to ryanodine (Levin et al., 1994a). Saito and colleagues (1994), however, have shown that the reduction in the contractile responses of isolated strips of obstructed rat detrusor are paralleled by changes in [Ca2+],; stimuli are less able to increase [Ca2+li, suggesting that altered calcium translocation or release may underlie the contractile changes.

8.2.

Changes

Leading

to Bladder

Znstability

As was made clear in Section 5.1.3, the association between outflow obstruction and bladder instability is well established. We have also suggested a link between obstruction and partial denervation, and have shown that actual or functional denervation leads to alterations in the properties of the smooth muscle cells. It has been postulated (Brading and Turner, 1994) that changes in the smooth muscle function consequent on reduction of activity in the intrinsic nerves may be a prerequisite for the development of instability. Evidence strongly suggests that in the rat (Igawa et al., 1992) and in the pig (Sethia et al., 1988; Brading and Turner, 1994), unstable bladder contractions are myogenic in origin. They persist in the rat after central pharmacological blockade of the micturition reflex, and in the pig when all the sacral spinal roots involved in the micturition reflex are severed. They also persist in animals in which all peripheral neuronal activity has been abolished by intravenous tetrodotoxin (Turner, 1997; the animals were artificially ventilated and the cardiac output and circulation maintained with intravenous noradrenaline). The production of spontaneous increases in intravesical pressure requires synchronous activation of the smooth muscle cells in the bladder wall. As described in Section 2.3, in normal detrusor, this is achieved mainly through the dense excitatory innervation of the myocytes, since the electrical coupling between the bundles seems to be poor. If the spontaneous rises are myogenic, as appears to be the case in some experimental models, then this will require some other mechanism for synchronous activation of the cells. An increase in the cell-to-cell electrical coupling would clearly be an appropriate mechanism, and there indeed is evidence to support this occurring in unstable bladders. In the pig, Fujii (1987) attempted to record electrical and mechanical activity from detrusor strips using the double sucrose-gap apparatus. In this approach, a strip of tissue is used and a central node is perfused with normal solution. On each side, the tissue is perfused with ion-free sucrose solution, and the ends of the strip are bathed again in saline solutions. Electrical activity is recorded extracellularly across one sucrose gap, and current can be injected into the nodal cells across the other. The technique relies on good electrical continuity between the cells in the sucrose gaps and works well in most smooth muscles (Burnstock and

Straub, 1958). Using bladder strips from the normal pig, however, Fujii was unable to get the technique to work. When he used strips from animals with unstable bladders, he was able to record activity, suggesting that the strips from unstable bladders were better coupled than the normal strips. Another manifestation of increased electrical coupling between cells in unstable bladders is the altered pattern of spontaneous mechanical activity. As mentioned in Section 2.1, fused tetanic contractions are not seen in normal bladder, but they have been recorded in strips from unstable human bladders (Kinder and Mundy, 1985a; Mills et al., 1997; German et al., 1995) and from unstable pig bladders (Turner, 1997). Elbadawi and colleagues (199313) have also suggested that smooth muscle cells in unstable bladders are better coupled electrically, and have demonstrated an increase in protrusion junctions between cells using electronmicroscopy. Coupling could also be achieved by a mixture of mechanical and electrical processes-the stretchactivated channels identified by Isenberg (Wellner and Isenberg, 1993a,b) could be involved. In the unstable pig, in viva recordings and observations of the behaviour of the animals and the effects of various drugs strongly suggest that the animals can be aware of the unstable bladder contractions, since they sometimes take up their normal micturition stance at each occurrence, whether or not urine leakage occurs. The frequency of such contractions during filling can be reduced by doses of atropine or hexamethonium sufficient to eliminate voiding contractions, although the occasional unstable contraction still occurs and may be associated with the normal behavioural response (Turner, 1997). It seems very likely that an element of the normal micturition reflex in some way is involved in the initiation of many, or most, unstable contractions in the conscious obstructed animal. A possible scenario is that as filling of the bladder progresses, the increasing activity in the sensory nerves in some way results in activation of a few of the most sensitive excitatory motor neurones, which cause contraction of some detrusor muscle bundles. In the normal bladder, this local activity will not spread and will have no effect on the intravesical pressure, although it may be responsible for activating a normally silent set of sensory nerve endings through local distortion (Coolsaet et al., 1993), leading to urgency. In obstructed bladders, the increased excitability of the smooth muscle, combined with the possibility that electrical signals spread more easily, may result in synchronous activation of the bladder wall and an increase in intravesical pressure-i.e., an unstable contraction. However, the persistence of unstable contractions in the presence of systemic tetrodotoxin indicates that neural activity is not an absolute requirement for their occurrence, and thus, that they can be of purely myogenic origin in this model.

8.3. Smooth Muscle

in the Diabetic

Bkdder

In comparison with work on obstructed bladders, there has been less work on the properties of bladders from diabetic

93

Bladder Smooth Muscle in Health and Disease animals. As stated in Section

7.1, most of the urodynamic

production

changes

are common

to all animal

into phosphatidylinositol

models of diuresis, whether or not diabetic,

the most obvi-

ous change

of the bladder

seen in micturition being an increased

wall and an increase micturition differences dition.

in the volume

is induced.

show rather

compliance

variable

Studies

threshold

on isolated

changes,

which

at which

preparations

may be due to the

in the length of time and severity of the con-

Most of the detailed studies have been carried out

The

evidence

In spite of swollen neurones

in the parasympathetic

put to the bladder described in Section

in-

7.2.1, the consensus

of opinion is that the motor innervation

is functionally

un-

for changes

substance

I’. Dahlstrand

of myo-inositol rat bladders.

in the sensory innervation,

to studies on the responsiveness

neurones, has led

of STZ-treated

and colleagues

bladders to

(1992)

found that

bladder strips became more responsive to substance less responsive to capsaicin, a sensory denervation

I’, but

suggesting that there might be

and denervation

K. Kamata and colleagues

supersensitivity

(1993)

to

found similar

results, but showed that the density of substance I? receptors in fact was decreased, suggesting that the increased sensitivity was due to an indirect effect through triggering a greater

impaired, at least over the range of times studied. In iso-

than

lated tissues, there is a variability

leagues (1994)

in the reported effects of

incorporation in STZ-treated

particularly damage to capsaicin-sensitive

substance

on rats.

and enhanced

normal

production

of prostanoids.

Pinna

and col-

also showed that although there was a pro-

STZ on the responses of the tissues to intrinsic nerve stimu-

gressive loss of the ability of capsaicin to cause contraction

lation, but most workers find only relatively small changes

of the isolated bladder in STZ-treated

compared with the controls.

reduction in the response to applied substance P and no im-

It should be remembered

in these animals, ATE’ and ACh are cotransmitters postganglionic changes

parasympathetic

motor

nerves,

that in the

and that

in the smooth muscle properties that might have

occurred in response to altered patterns of input could play a role in altered responsiveness trinsic nerve stimulation, the neurones. contractile carinic

Several

of the smooth muscle to in-

as well as pathological

papers describe

changes in

an increase

in the

response of tissues from treated animals to mus-

agonists (Latifpour

et al.,

1989,

1991; Belis et al.,

1992; Kamata et al., 1992; Longhurst et al., et al.,

1994;

change

(Lincoln

et al.,

Mimata et al.,

1995).

1984a,b;

1992; Tammela

Others

Malmgren

found little et al.,

198913;

Luheshi and Zar, 1991), and yet, others a reduced response (Longhurst

and Belis,

1986).

Moss and colleagues (1987) ness to a purinergic

In isolated

whole bladder,

found an increased responsive-

agonist and a somewhat

sponsiveness to ACh 8 weeks after treatment,

reduced rebut a reduced

pairment

in the cholinergic

prostaglandin

formation

suggested by Tammela crease in spontaneous

animals, there was no

motor innervation.

in STZ-treated

et al. (1994) mechanical

Increased

animals has been

to account

for an in-

activity that was seen.

There also have been several studies on the sensitivity of tissue from STZ-treated leagues (1992)

rats to calcium. Longhurst and col-

found an increased sensitivity

sot to calcium, and Belis and colleagues

of the detru-

(1991,

1992) pro-

posed that there may be alterations in Ca2+-channel

activity

in diabetic animals. Kamata and colleagues (1992)

provide

evidence suggesting an increase in Cal+ influx through receptor-operated, Hashitani

but not voltage-operated,

and Suzuki (1996)

to study the electrophysiological from STZ-treated spontaneous

animals,

electrical

Cal+ channels.

have used microelectrodes properties of the bladder

and found that there was less

activity, a supersensitivity

of the de-

polarisation to muscarinic receptor agonists, and a reduced abil-

response to the purinergic agonist and a normal response to

ity of excitatory junctional potentials to trigger an action po-

ACh

tential,

after 16 weeks. Luheshi

smaller neurogenic

contractile

but no changes in sensitivity duced change

release

and Zar (1990a)

of the

response in treated animals, to ACh,

noncholinergic

in responsiveness

and suggested a retransmitter.

and Levin,

of diuresis led to the conclusion

diabetic rats (Long-

1991).

parison by Eika and colleagues (1994a)

A careful com-

of the three models

that the contractile

implying

a reduced

release of neurotransmitters.

They also found that the postjunctional Na+-K+ pump was less able to generate hyperpolarisation on readmission of potassium.

Little

to agonists or nerve stimulation

was found in strips from spontaneously hurst, 1991; Longhurst

found a

func-

9. TREATMENT 9.1.

OF THE

UNSTABLE

BLADDER

Introduction

There are numerous treatments for bladder instability. They can be grouped into behavioural

and electrostimulation

tions were the same in all three models and did not differ

treatments, drug treatment,

significantly

gical treatment generally is more effective in mild to moder-

from normal animals.

Efforts have been made to account sponsiveness of the STZ-treated tor stimulation.

for the increased re-

bladders to muscarinic recep-

Studies on the binding of the muscarinic

receptor antagonist

[3H]QNB have demonstrated

receptor numbers, in both STZ-diabetic

increased

and sucrose-fed di-

uretic rats, but no change in affinity (Latifpour et al., 1989, 1991). Muscarinic

receptor stimulation

part through IP3-mediated

is thought to act in

release of calcium from the sar-

coplasmic reticulum. Studies on phosphoinositide hydroly sis (Mimata et al., 1995) have demonstrated enhanced IP3

and surgical treatment.

Nonsur-

ate instability than in severe instability. There is no specific treatment for the diabetic bladder; treatment of instability in diabetes is not specifically different from that in other conditions and is discussed below. Outflow obstruction

is treated

either with ol-adrenergic blockade or with bladder outlet surgery, and hypocontractility is not specifically treatable (although significant

residual urine in the absence of obstruc-

tion is treated with clean intermittent catheterisation). There are several problems in assessing the effects of treatment of instability. The undoubted influence of the

W. H. Turner and A. F. Brading

94

mind over micturition behaviour may produce considerable placebo effects. Indeed, a placebo response of 30% or more typically occurs in trials of drug treatment of instability, and this probably applies to all forms of treatment. Real fluctuations in the severity of instability probably also occur in many patients, in addition to any apparent fluctuations due to the limited sensitivity of urodynamics. These factors necessitate controlled trials and render uncontrolled data of very limited value, although with physical treatments, a satisfactory placebo may not be possible. Many of the drugs used so far to treat instability have side effects, and so in cross-over studies, the patient or the investigator may not be blind to treatment. There is also evidence that in drug trials, improvements may decrease somewhat with longterm study (Sonoda et al., 1989), so enthusiasm over the results of less than, say, 1 month’s treatment should be tempered. Many reports describe patients who become symptom free as cured, which is clearly a misconception, and they may not remain symptom free off treatment. A further problem is that no form of treatment currently licensed for detrusor instability was introduced after any kind of rational laboratory testing programmes, so thorough scientific support for all treatments is lacking or tenuous. Once a treatment is in clinical use, determining its efficacy may be difficult because of the problems of doing a satisfactory clinical trial. Thus, with some exceptions, many treatments have been assessed in small, badly designed studies, from which objective evidence cannot be obtained. The treatments are then judged on clinical impression and on often selective interpretation of existing trial data, so the unsatisfactory treatment of instability is hardly surprising. Finally, the question of symptoms and urodynamics needs to be addressed. Symptoms are what concern the patient, and although it can be argued both that a symptomfree patient needs no further assessment and that an incontinent patient who becomes totally dry must at least have smaller unstable contractions than before treatment, clearly patients can become symptom free with persistent instability. In addition, no conservative treatment improves more than about two-thirds of patients, and in many patients, the treatment effect is a matter of degree rather than a clear-cut one, so symptomatic assessment has limitations. Patients with incontinence due to instability seem intuitively unlikely to become dry unless their unstable contractions are diminished, so this is an overwhelming reason for finding a treatment that abolishes instability, rather than one that improves symptoms without affecting unstable contractions. Therefore, despite its limitations, urodynamics should always be used in treatment development and in the clinical assessment of its outcome, so that treatments that abolish instability can be identified and pursued.

9.2. Behcwiourd

and Electrical Treatments

Conceptually, the simplest conservative treatment for instability is bladder training. This involves the patient progressively increasing the interval between voids, suppressing

the urge to void by whatever mental efforts are necessary. The arbitrary end-point is when the patient feels that the interval has become acceptable, and thus, their symptoms of frequency and urgency are no longer troublesome. After in-patient instruction of women with incontinence and instability, 84% became continent and 76% symptom free, compared with 56% continent and 48% symptom free in incontinent women treated with flavoxate and imipramine (Jarvis, 1981). Of all women, 94% of those who became continent had also become stable, whilst all those who remained incontinent remained unstable (Jarvis, 1981). This underlines the need for treatment that renders patients stable. Not surprisingly, no side effects from bladder training were seen. Psychotherapy significantly decreased incontinence (by about 50%) in a three-way randomised comparison with bladder training and propantheline, but no significant urodynamic improvement occurred (Macaulay et al., 1987). In a group of women treated primarily by bladder training, biofeedback rendered 74% substantially or totally symptom free (Millard and Oldenburg, 1983). After 1 month of hypnosis in 50 incontinent women with instability, 29 became totally symptom free and 14 improved considerably (Freeman and Baxby, 1982). Of those who had posttreatment urodynamics, 73% were either stable or less unstable. Fip nally, acupuncture reduced symptoms in 10 of 13 patients with instability, but no urodynamic improvement occurred (Philp et al., 1988). Several types of electrical stimulation have been used in the treatment of instability. Although the stimulation in some cases may have an apparently rational design, and there is good reason to believe that some types of stimulation may actually suppress unstable contractions, in reality, it is far from clear what is actually being stimulated and which pathways are involved. It should be remembered that when nerves are stimulated with extracellular electrodes, which nerve fibres will be depolarised to threshold and fire an action potential will depend both on the size of the axon and its position with respect to the applied electrical field. In general, the larger the nerve fibre and the closer it is to the depolarising electrode, the more easily it will be activated. Fibres are classified by their size and myelination. A fibres are the larger myelinated fibres, B fibres are small my elinated fibres, and C fibres even smaller and unmyelinated. Nerves conducting the sharp components of painful stimuli are amongst the smallest A fibres. The preganglionic nerves are B fibres, whereas the postganglionic fibres and many of the neurones mediating signals in the autonomic reflexes are C fibres. In a mixed nerve, it will be virtually impossible to excite B or C fibres without causing intolerable pain. The most likely fibres to be excited are the large somatic motor axons, which mostly innervate the distal muscles (hence flexure of the big toe is often seen when motor roots are stimulated) and sensory neurones from muscle spindles. More selective motor or sensory stimulation can be achieved by activating the ventral or dorsal roots separately. Skeletal muscle fibres themselves are more

Bladder Smooth Muscle in Health and Disease easily excited

by field stimulation

95

than their nerves, and

any stimulus that activates skeletal muscle (e.g., pelvic floor muscles)

may indirectly

stimulate

proprioceptive

sensory

neurones. Interestingly, these neurones are also likely to be activated during voluntary contractions of the pelvic floor muscles and may be activated by acupuncture; lation of the excitability

of neurones

flex pathway by collaterals

thus, modu-

in the micturition

of proprioceptive

re-

afferents is a

possibility. Intravaginal

and anal stimulation

aim of inhibiting inhibitory

bladder motor neurones

sympathetic

Intravaginal

is carried out with the and activating

fibres (Fall and Lindstrom,

or anal stimulation,

or both, improved or abol-

ished symptoms in 83% of patients with instability et al., 1989);

urodynamics

of 41 patients,

1991). (Eriksen

showed stable bladders in 54%

and all stable patients

free (Eriksen et al., 1989).

remained

symptom

After lower limb nerve stimula-

tion, 12 of 15 patients with instability

or hyperreflexia

came stable and dry (McGuire

1983),

et al.,

be-

although

an

acute study in paraplegics showed no effect (Eriksen et al., 1989). ished 1992).

Dorsal penile nerve stimulation hyperreflexia Thirteen

of 24 incontinent

came continent transcutaneous trodes),

inhibited

in six paraplegics

or abol-

(Wheeler

unstable

et al.,

patients

be-

and 11 became stable after S3 dermatome electrical

whereas

nerve stimulation

control

matome was ineffective

stimulation (Webb

has been interest recently

(with pad elec-

over the T12

and Powell,

1992).

in the use of electrical

derThere

stimula-

tion of somatic nerves in the sacral roots to modulate the behaviour

of the lower urinary tract (Dijkema

Bosch and Groen, stimulation

placed electrode

that symptoms are alleviated by neuromodulation, surgical operation electrode

can be done to implant

and a stimulator

box. Recently,

the sacral anterior roots through magnetic been tried in an experimental patients with hyperreflexia contractions

a permanent

stimulation

has

of the

detrusor

though the results so far are preliminary,

by rapid in-

magnetic stimu-

applied just before provocation

reduction

of

et al., 1996). Unstable

fusion of fluid into the bladder. Functional lation of S2-S4

an open

stimulation

were provoked during cystometry

a profound

shows

study on spinal cord injured

(Sheriff

Drug Treatment

Numerous drug treatments

exist for bladder instability.

Be-

cause the problem was originally believed to be an overactive micturition

reflex

arc, anticholinergics

were given.

Several drugs with wholly or partly anticholinergic

activity

have been used with mixed success. They appear to abolish instability in some patients, but in all patients, they inevitably impair detrusor excitation

somewhat, tending to reduce

voiding pressure and causing residual urine. Depending

on

efficacy and dose, this may become a clinical problem. Most drugs in clinical use, and certainly

all with anticholinergic

activity, have side effects that often limit dosage or necessitate treatment

withdrawal. Indeed, many clinicians

ticholinergics

by titrating

(Massey

and Abrams,

with drug treatment

them

1986),

until

use an-

side effects

occur

a practice

hard to imagine

of other conditions.

It should also be

stressed that peripheral and central effects generally cannot be distinguished

in clinical trials, and this may even be dif-

ficult experimentally.

conclusions

about the site

of action of drugs and about the implications

Therefore,

for the patho-

physiology of the disorder must be cautious. In those cases when hyperreflexia

is not the cause of instability,

the ratio-

nale for the use of antimuscarinics

is less clear; however, if

the scenario

8.2 has any relevance,

outlined

in Section

then one could speculate that low doses of muscarinic

an-

tagonists might reduce the initial activity in the postganglionic nerves suggested to result in urgency and thus, relieve some of the troublesome

symptoms of the unstable bladder.

et al., 1993;

1995; Koldewijn et al., 1994). If a trial of

using a percutaneously

9.3.

resulted in

contraction.

Al-

they are very en-

9.3.1.

Atropine.

As would be expected,

dose, intravenous

at a sufficient

atropine can abolish the micturition

re-

flex in humans and old world monkeys

in which the re-

sponse of the detrusor to parasympathetic

nerve stimulation

is purely cholinergic

(Craggs and Stephenson,

1985; Craggs

et al., 1986), whereas in animals with a significant gic component

puriner-

such as the guinea-pig or rat, intravenous at-

ropine reduces the voiding pressure, increases the frequency of micturition,

and leads to the development

of a residual

volume (Peterson et al., 1989; Iagawa et al., 1994). In unstable animal models, atropine was not very effective at abolishing

the unstable contractions.

unstable mini-pigs given 0.02-0.1

In conscious

mg/kg intravenous

atro-

couraging,

and there seems little doubt that this technique

pine, voiding pressure fell significantly,

will come

to occupy

tractions were only affected at a dose that abolished voiding

drug treatment,

and surgical treatment, ries morbidity

a valuable

middle ground between

which is currently

of very limited success,

which is highly effective,

and mortality.

How precisely

tion produces its effects, at a physiological

but car-

this stimula-

level, remains to

be determined. Behavioural treatments and electrical stimulation seem to produce some clinical benefit without obvious side effects; it is unfortunate, to be overlooked

therefore,

that such treatments

in favour of drug treatment.

tend

Data from

both treatment groups also underline the influence of neural factors in clinical instability. However, their time-consuming nature make them unsuitable for widespread use.

(Speakman,

but unstable con-

1988). In the conscious obstructed rat, 1 mg/kg

atropine into the distal aorta increased bladder capacity by 35%, reduced voiding pressure by 25%, and led to residual urine, but had no effect on unstable contractions al., 1994). In contrast,

(Igawa et

in humans with unstable bladders, atropine

is more effective. Intravenous atropine at 0.017 mg/kg depressed or abolished unstable contractions in hyperreflexic patients (Lapides, 1958). In children given 0.007-0.14 kg subcutaneous

atropine,

hyperreflexia

was reduced

mg/ or

abolished (Naglo et al., 1981). In unstable of hyperreflexic patients, intravesical atropine increased capacity and re-

96

W. H. Turner and A. F. Brading

duced incontinence; one hyperreflexic patient became stable (Ekstrdm et al., 1993). Of 12 hyperreflexic patients given intravesical atropine, 5 could not retain the solution (presumably because of gross instability), but in 6 of the rest, capacity increased and instability decreased (Glickman et al., 1992). No side effects were noted in either study of intravesical atropine. Thus, there does seem to be evidence in favour of the efficacy of atropine in instability in humans, clinically and experimentally, but the efficacy of other drugs with significant anticholinergic activity has not been so well established. 9.3.2. Propantheline. Propantheline is an antimuscarinic, producing some ganglion blockade (Finkbeiner et al., 1977). In human detrusor strips, propantheline has similar antimuscarinic activity to atropine (H. G. A. Naerger, personal communication). It inhibited carbachol-induced contraction of mini-pig detrusor strips with a similar potency to atropine (Peterson et al., 1990). In rabbit detrusor strips, it was as potent as atropine at inhibiting muscarinic agonistinduced contraction and equally ineffective at inhibiting barium chloride-induced contraction (Anderson and Fredericks, 1977). Five of six men with prostatic enlargement given 30 mg of propantheline could not void (Kieswetter and Popper, 1972). Voiding pressure after propantheline was reduced by 47% in conscious mini-pigs (Peterson et al., 1990), by 25% in the dog (Tulloch and Creed, 1979), and by 53% in the guinea-pig (Peterson et al., 1989); considerable residual urine developed in the mini-pig. In unstable or hyperreflexic patients given propantheline 15 mg intramuscularly (Blaivas et al., 1980), unstable contractions were abolished in 79%, but the effect on voiding was unclear. Oral propantheline, 15 mg 3 times daily, produced no subjective or urodynamic improvement over placebo, or residual urine (Thtiroff et al., 1991), although 30 mg 4 times daily reduced incontinence 17% more effectively than placebo (Zorzitto et al., 1986). The ratio of side effects from propantheline and placebo was about 2:l (Thuroff et al., 1991) and 4:l (Zorzitto et al., 1986). The effects of propantheline given acutely and chronically seem to differ, perhaps because the dosage used acutely was supramaximal and abolished instability at the expense of voiding, whereas the bioavailability after oral administration is low, so voiding is preserved, and there is less effect on instability. This is unclear because of the lack of data on voiding after parenteral propantheline, but the apparent inevitability of side effects from parenteral dosage (Blaivas et al., 1980) suggests it is so.

9.3.3. Oxyburynin. Oxybutynin has anticholinergic, smooth muscle relaxant and local anaesthetic actions (Lish et al., 1965). In human and rabbit bladder strips, oxybutynin moderately inhibited barium chloride-induced contraction (Anderson and Fredericks, 1977), and was a less potent antimuscarinic than atropine or propantheiine in human (H. G. A. Naerger, personal communication), minidpig (Peterson et al., 1990) and rabbit detrusor strips (Anderson and Fredericks, 1977). Although twice as potent a local anaesthetic as lignocaine on the rabbit cornea (Lish et al., 1965), it inhibited frog sciatic nerve conduction with only about two-thirds the potency of tetracaine (Fredericks et al., 1978), so its local anaesthetic potency may be modest. The anticholinergic potency of oxybutynin is around 1000 times greater than its local anaesthetic potency and 100 times greater than its antispasmodic potency (Anderson and Fredericks, 1977; Fredericks et al., 1978). There was no significant Cal+-channel antagonist activity in rabbit detrusor (Malkowicz et al., 1987). Spontaneous activity of rat detrusor strips was not inhibited by oxybutynin, and the maximum reduction in the response to nerve-mediated contraction was 41% (Morikawa et al., 1988). No published data exist on the effect of oxybutynin on normal human bladder function. In conscious animals, oxybutynin reduced voiding pressure by 65% in the mini-pig (Peterson et al., 1990), 83% in the rat (Guarneri et al., 1991a), and 77% in the guinea-pig (Peterson and Noronha-Blob, 1989): residual urine was slight in the mini-pig, considerable in the guinea-pig, and not estimated in the rat. Data from some placebo-controlled clinical trials that assessed oxybutynin urodynamically in instability and hyperreflexia (Moisey et al., 1980; Tapp et al., 1990; Thuroff et al., 1991) is shown in Table 1. In each of these studies, oxybutynin improved symptoms significantly compared with placebo, although not always substantially [74% vs. 9% (Moisey et al., 1980) and 67% vs. 50% (Thuroff et al., 1991)]; the capacity increase was generally 20110%. The amount of residual urine usually was small, but frequent side effects often led to treatment withdrawal; oxybutynin was described as an effective, but ‘. . . relatively unpleasant drug . , . .’ (Tapp et al., 1990). Urodynamic stability during oxybutynin treatment occurred in 9% (Moisey et al., 1980) and 62% (Tapp et al., 1990) of patients, compared with 4% and 42%, respectively, with placebo. Intravesical oxybutynin has also been used to try to improve efficacy and reduce side effects; this could be suitable for those unstable patients who self-catheterise already. Although

no placebo-controlled

studies have

been done,

TABLE 1. Placebo-Controlled Trials of Oxybutynin in Detrusor Instability and Hyperreflexia Author: Dose Moisey et al., 1980: 5 tds Thtiroff et al., 1991: 5 tds Tapp et al., 1990: 5 qds Values are shown as oxybutynin

Symptomatic improvement

Capacity increase

Residual urine

Side effects

Withdrawals

74% vs. 9% 67% vs. 50% 0

0 80 vs. 23 60 vs. -14

0 27 vs. -2 74 vs. -7

74% 63% vs. 33% 94% vs. 32%

22% 3% vs. 0 32% vs. 0

vs. placebo or as oxybutynin

alone. Doses in mg, volumes in mL.

97

Bladder Smooth Muscle in Health and Disease larger series showed improved continence ble or hyperreflexic

Intravesical

in 55% of unsta-

terodiline

increased bladder capacity mark-

edly in 5 of 12 hyperreflexic

patients who have failed oral treatment

patients,

but no changes oc-

(Weese et al., 1993). In fact, systemic levels are higher with

curred in unstable patients

intravesical

scious obstructed rats, terodiline,

like oxybutynin,

no urodynamic effects (Guameri

et al., 1991b).

al.,

compared with oral administration

1992),

(Massad et

and side effects do occur after intravesical

use

Thus, overall, there is no consistent

(Kasabian et al., 1994). Unlike

its effect in the unobstructed

conscious

rats,

(EkstrGm et al., 1992).

neither

voiding

for the efficacy of terodiline,

rat, in obstructed

pressure,

premicturition

In conproduced

objective

evidence

despite strong clinical impres-

sions to the contrary. Terodiline

has now been withdrawn

contractions, nor residual urine were affected by oxybutynin (Guarneri et al., 1991b). This could imply reduced cho-

because of apparent cardiac side effects (Connolly

linergic excitation

(see Section

ity to purinergic

in the obstructed rat; increased sensitivtransmission

in the conscious

cant noncholinergic,

nonpurinergic

rat is an alternative

However,

Guaneri’s

transmission

(Luheshi

findings question

9.3.5.

signifi-

in the ob-

9.3.10).

Flavoxate.

The

phosphodiesterase

and Zar, 1990b).

local anaesthetic

properties

inhibition,

Terodiline.

voxate antagonised Terodiline

has

activity,

times less than atropine similar local anaesthetic 1984). Nerve-mediated

and nifedipine,

sues other

than

ericks et al., 1978) and no Ca 2+-channel

respectively,

and

and carbachol-induced

human detrusor were inhibited tively, by terodiline

minimal anticholinergic

100

activity to lignocaine

the bladder,

(Malkowicz et al., 1987). However, in guinea-pig tissues, reonism in taenia coli, and equivalent local anaesthetic

activ-

ity to lignocaine

1985).

respecIn tis-

The mechanism

it had weak Cal+-channel

properties,

up to 1000 times less than nifedipine

(Larsson

Backstriim

et al.,

with

about

500

weaker

than

Systemic

terodiline

verse reactions

atropine

changes (Ekstrijm et al., 1992). travenous terodiline in the rat (Guameri

et al., 1991a);

of patients

and Catanzaro,

1980);

in 45%

other studies,

however, showed little or no effect (Cardozo and Stanton,

et al., 1990) and 62%

1979).

there was little residual

Data from some placebo-controlled (Peters,

clinical

urodynamically

1984; Ulmsten

In placebo-controlled

significant

no consistent

subjective

trials of flavoxate,

improvements

only

one found

with

placebo

ther subjective nor objective changes (Chapple et al., 1990).

and

1985; Tapp et

9.3.6.

patients often im-

subjective

occurred with ten&line

trials that

in instability

et al.,

al., 1989) is shown in Table 2. Although improvement

(Zanollo

(Meyhoff et al., 1983), and a urodynamic study showed nei-

have assessed terodiline

proved subjectively,

Intravenous

Intravenous flavoxate reduced unstable contractions

of in-

urine in the mini-pig.

hyperreflexia

1968).

der capacity increased by up to 39% (Guameri et al., 1991a).

in conscious animals, voiding pressure

fell by 44% in the mini-pig (Peterson

and Morales,

in the dog and 13% in the cat (Morikawa et al., 1988). In the conscious rat, voiding pressure was unaffected, but blad-

produced no urodynamic After administration

(Kohler

flavoxate reduced voiding pressure under anaesthesia by 3%

has not been studied in normal subterodiline

flavoxate slightly increased bladder capac-

ity and decreased resting bladder pressure, with no acute ad-

(Peterson et al., 1990). Terodiline, therefore, appears to be a rather weak antimuscarinic and Calf-channel antagonist. jects, but intravesical

(Cazzulani et al., 1984,

of action, if any, of flavoxate on the detru-

In volunteers,

The carbachol-induced

times

occurred

antag-

sor thus is uncertain.

of mini-pig detrusor were inhibited by terodiline,

a potency

activity (Fred-

antagonist activity

responses of

blocking

contractions

or local anaesthetic

ductions in ureteric activity, moderate Cal+-channel

K. E. et al., 1988).

1985).

produced by 80

(Andersson,

by 29% and 45%,

(Andersson,

and

and in rabbit detrusor, it had

and

at

include

blockade,

weakly the contraction

least

anticholinergic

although

flavoxate

activity; its effect is smooth muscle relax-

mM K+ (Caine et al., 1991), 9.3.4.

of

Ca2+-channel

ation (Cazzulani et al., 1984). In human detrusor strips, fla-

the basis of the rat

model of instability.

Ca2+-channel-blocking

et al.,

but study of this family of drugs remains of interest

obstructed

rat supports this (Igawa et al., 1994). A functionally structed

1991),

Calcium-channel

rapamil block calcium

or objective

channels

compared with pla-

muscle

antagonists.

Nifedipine

ion entry through

and so, with varying selectivity, contraction

(Rang

and Dale,

inhibit

1991).

cebo. The placebo response in some studies was marked, sug

abolished

gesting that the study protocols may have had some effect.

and greatly reduced the response to carbachol

responses to barium chloride

and ve-

L-type calcium smooth

Nifedipine

and 127 mM K+, in human de-

TABLE 2. Placebo-Controlled Trials of Terodiline in Detrusor Instability and Hyperreflexia Author: Dose Peters, 1984: 37.5 Tappet al., 1989: 25-75 Ulmsten et al., 1985: 37.5

Subjective improvement

Capacity increase

Residual urine

Side effects

26% vs 7%1 62% vs: 42% 100% vs. 17%

53 vs. 6 55 vs. 43

0 vs. 0 8 vs. 12

55% vs. 42%

19% vs. 0

29%

15% vs. 11%

70 vs. 0

Values are shown as terodiline vs. placebo. Doses in mg/day, volumes in mL. ‘Mean reduction in incontinent episodes. 2Drv mouth.

45 vs. 9

vs. 11%2

3% vs. 8%

Withdrawals

0% vs. 0%

W. H. Turner and A. F. Brading trusor strips (Forman et al., 1978). The nerve-mediated response of human detrusor strips was only reduced by about 50% by nifedipine (Fovaeus et al., 1987), and it was sug gested that the response to exogenous muscarinic agonist and nerve-mediated ACh release may differ, with voltagesensitive calcium channels being important in nerve-mediated contraction. This suggested a potential therapeutic role for nifedipine in instability. Resting bladder pressure was unchanged after nifedipine in stable women (Forman et al., 1978), but voiding pressure decreased in the conscious rat by 71% (Guarneri et al., 1991a). In unstable or hyperreflexic women, nifedipine acutely reduced the frequency and amplitude of unstable contractions and increased bladder capacity (Rud et al., 1979); all patients improved subjectively after a week of treatment. Subjective and objective improvement also occurred in an uncontrolled study of diltiazem (Faustini et al., 1989). Incontinence improved in hyperreflexic patients, with intolerable side effects from oral oxybutynin, who were given verapamil (Bodner et al., 1989). Intravesical verapamil somewhat increased mean bladder capacity in hyperreflexic patients (Mattiasson et al., 1989). Nifedipine given to conscious obstructed rats did not affect voiding pressure, but reduced the frequency of unstable contractions by 55% (Guarneri et al., 1991b). However, despite some clinical and experimental evidence suggesting potential benefit from Ca*+-channel blockers, they have found no place in clinical practice.

9.3.7. Imipramine. Imipramine has several properties: it inhibits noradrenaline reuptake and it has muscarinic receptor, cy2-adrenoceptor and Ca*+-channel antagonist activity (Malkowicz et al., 1987; Rang and Dale, 1991). Imipramine has about 500 times less antimuscarinic activity than atropine on mini-pig detrusor strips (Peterson et al., 1990). An a-adrenoceptor blocking action was also suggested by its potentiation of the detrusor relaxation by noradrenaline seen in canine detrusor (Lipshultz et al., 1973). A local anaesthetic potency similar to that of tetracaine was observed (Fredericks et al., 1978), and significant Ca2+-channel antagonist activity occurred in detrusor strips from the rabbit (Malkowicz et al., 1987) and the rat (Olubadewo, 1980). Increased spontaneous activity of guineapig and rat detrusor strips has been observed (Dhattiwala, 1976), although the opposite also occurred in rat strips (Olubadewo, 1980). Taken together, this data suggests that imipramine has multiple actions, and ascribing any clinical effect on the bladder to one particular action may well be impossible. The evidence for its efficacy in instability and hyperreflexia is weak. Some subjective and objective improvement occurred in hyperreflexic patients (Cole and Fried, 1972), but no acute urodynamic effect occurred (Cardozo and Stanton, 1979). A randomised placebo-controlled trial showed no improvement with imipramine compared with placebo (Castleden et al., 1986). In the rat, voiding pressure was reduced by 17% and spontaneous contractions were

reduced in amplitude al., 1989~).

by 33% by imipramine

(Morikawa

et

9.3.8. ycAminobutyric acid receptor agonists and antagonists. Baclofen, a GABA-B receptor subtype agonist, inhibits reflex activation of motor neurones (Rang and Dale, 1991). Baclofen did not affect either the response to electrical field stimulation or to ACh of human detrusor strips (Ayyat et al., 1984), but some reduction in the nerve-mediated response occurred, with baclofen acting via GABA-B receptors in both rabbit and human detrusor (Chen et al., 1992, 1994). This suggests a peripheral site of action for baclofen in the treatment of detrusor instability. Nervemediated response in human strips was unaffected by GABA-B receptor antagonism, suggesting no physiological modulatory role for GABA (Chen et al., 1994). Intravenous baclofen increased bladder capacity in the rat and dog (Morikawa et al., 1989b), but not the conscious rat (Morikawa et al., 1989a,c). Intrathecal baclofen abolished spontaneous bladder contractions in the rat (Morikawa et al, 1989b) and greatly increased compliance in the dog (Magora et al., 1989). Intrathecal saclofen, a GABA-B antagonist, had no effect on voiding in the conscious rat (Igawa et al., 1993). In paraplegic patients given baclofen to reduce skeletal muscle spasticity, the impression that it improved bladder symptoms led to its use to treat instability and hyperreflexia. Over one-half of 40 unstable patients given baclofen improved subjectively, but no improvement compared with placebo was shown (Taylor and Bates, 1979). Acute and chronic intrathecal dosage abolished unstable contractions and increased bladder capacity in hyperreflexic patients implanted with a pump system for intrathecal baclofen to treat limb spasticity (Steers et al., 1992). In the conscious obstructed rat, intrathecal and local intraarterial baclofen increased spontaneous contractions (Igawa et al., 1993). Taken together, these results suggest that central GABA receptor activation can inhibit the micturition reflex. There is some clinical evidence of benefit in patients with hyperreflexia. 9.3.9. Potassium-channel agonists. The membrane potential depends on the membrane’s ionic permeability and the transmembrane ionic concentration gradients. For each ion, there is a membrane potential (equilibrium potential) that balances the ion’s tendency to move down its concentration gradient. This potential is usually close to that of the most permeant ion, generally K+. K+-channel openers (KCOs) activate membrane potassium channels and increase membrane K+ permeability, thus hyperpolarising the cell. This, in turn, reduces the excitability of the cell, .and may also reduce the agonist-stimulated intracellular calcium rise necessary for contraction (Bray and Quast, 1991). Spontaneous mechanical activity is also reduced, although not necessarily due to hyperpolarisation (Brading and Turner, 1996). The reduced smooth muscle cell excitability produced by KCOs suggested that they might be useful drugs in detrusor instability (Speakman, 1988).

99

Bladder Smooth Muscle in Health and Disease Cromakalim and pinacidil reduced voiding pressure by up to 18% in conscious normal rats, but no other urody namic effects occurred (Malmgren et al., 1989a). A normal mini-pig given cromakalim voided at normal pressure (Speakman, 1988). Cromakalim abolished spontaneous activity in detrusor strips from stable and unstable human and pig bladders (Foster et al., 198913; Nurse et al., 1991); pinacidil had the same effect on control human bladder strips (Fovaeus et al., 1989). No significant reduction by cromakalim of the maximum response to electrical field stimulation occurred in strips from humans, the pig, and stable and unstable mini-pigs (Foster et al., 1989b), although a reduction occurred in strips from stable and unstable human bladder with cromakalim (Nurse et al., 1991) and in strips from control bladders with pinacidil (Fovaeus et al., 1989). Shifts to the right, indicating reduced responsiveness, were seen in the muscarinic agonist dose-response curves in each of these studies. The actions of cromakalim on detrusor are antagonised by glibenclamide, suggesting that cromakalim acts on ATPsensitive K+ channels [e.g., on human and guinea-pig detrusor strips (de Moura et al., 1993; Foster et al., 1989a)]; this is supported by electrophysiological data using human tissue (Wammack et al., 1994). In pig and guinea-pig detrusor, cromakalim increased potassium permeability and hyperpolarised the cell membrane (Foster et al., 1989a,b). In rat detrusor, cromakalim reduced spontaneous activity and the responses to field stimulation, carbachol and high K+, and for each effect, greater responsiveness was seen in tissue from obstructed rats than from controls (Creed and Malmgren, 1993; Malmgren et al., 1990a). Cell membrane hyperpolarisation was caused in rat detrusor by cromakalim (Creed and Malmgren, 1993) and in guinea-pig detrusor by pinacidil (Seki et al., 1992b). In guinea-pig and rat detrusor, levcromakalim and cromakalim open ATP-sensitive K+ channels (Bonev and Nelson, 1993a; Zhou et al., 1995), and in guinea-pig detrusor, muscarinic receptor activation is linked to inhibition of these channels (Bonev and Nelson, 1993b). Because ATP-sensitive K+ channels may contribute to repolarisation and to maintaining a normal membrane potential, the association with muscarinic receptor activation would provide a link between excitatory innervation and detrusor excitability, whereby muscarinic receptor blockade in pathologically excitable tissue (i.e., unstable detrusor) might act indirectly on K+ channels. A new KCO, YM 934, is also believed to open ATP-sensitive K+ channels in human detrusor (Masuda et al., 1995), and caused hyperpolarisation in guinea-pig detrusor, where it abolished spontaneous action potentials before it caused hyperpolarisation, suggesting that hyperpolarisation might not be the sole mechanism by which KCOs reduce detrusor excitability (Hashitani et al., 1996). In guinea-pig detrusor, a battery of K+-channel antagonists increased spontaneous activity, suggesting that there may be more than one type of K+ channel present in the detrusor (Fujii et al., 1990). Different K+-channel subtypes may also explain differences in the sensitivity of KCOs for

different tissues. Various KCOs were compared on rat portal vein and detrusor, and none showed bladder selectivity (Edwards et al., 1991). The existence of different K+-channel subtypes raises the possibility of developing a more or less bladder-specific KCO, which might avoid cardiovascular side effects. Cromakalim reduced urinary frequency and increased voided volume in 35% of unstable and hyperreflexic patients in an uncontrolled study (Nurse et al., 1991). In unstable patients, pinacidil produced no significant changes compared with placebo (Hedlund et al. , 199 1) . Intravenous levcromakalim produced no clinically significant urodynamic change in hyperreflexic patients (Komersova et al., 1995). In conscious obstructed rats, pinacidil and cromakalim reduced voiding pressure by 61% and 27%, respectively, and reduced spontaneous bladder contractions by 74% and 78%, respectively; both produced some residual urine (Malmgren et al., 1989a). Local intraarterial pinacidil tended to reduce voiding pressure, increase capacity, and produce residual urine; however, spontaneous contractions were virtually abolished (Igawa et al., 1994). Intravenous cromakalim abolished instability in three conscious unstable mini-pigs, but preserved voiding (Speakman, 1988). In the ‘hyperreflexic’ rabbit with acute penile ligation, intravesical pinacidil reduced the amplitude, but not the frequency, of phasic contractions and blood pressure was unaltered, whereas intravenous pinacidil caused hypotension without affecting phasic contractions (Levin et al., 1992). Thus, experimental evidence suggests that KCOs can abolish unstable contractions without preventing voiding, supporting their use in the treatment of instability. The poor clinical effect may be due to lack of sensitivity for bladder K+ channels. A preliminary report of the in viva activity of a new KCO, ZD6169, suggested bladder selectivity (Howe et al., 1995), although the assessment parameters (a reduction in voiding frequency in rats and a reduction in the bladder pressure at an infused bladder volume of 150 mL in dogs) were questionable.

9.3.10. Darifenacin and tolterodine. Two new agents, darifenacin and tolterodine, will appear shortly on the market for the treatment of instability. Both are muscarinic receptor antagonists, but there is controversy about their relative bladder selectivities in viva (Nilvebrandt et al., 1995; Newgreen et al., 1995). Until published clinical trial data appears, further comment about their role is not possible.

9.4. Surgery Early surgical treatments aimed to denervate or decentralise the bladder because of presumed micturition reflex arc overactivity. All were introduced empirically, and most have been abandoned because of poor long-term results. Prolonged bladder distension resulted from a belief that cystoscopy benefited some unstable patients, probably because of transient distension (Dunn et al., 1974). Of 20

100

patients, 19 were improved initially or symptom free, and 14 became stable, but these results were not sustained, and only 10% were symptomatically improved at 4 years (Smith, 1981). Transvesical phenol injection to cause ablation of the pelvic plexi subjectively improved 40% of unstable women and 84% of hyperreflexic women (Murray et al., 1986). Urodynamics showed that 49% were either stable or less unstable. However, because of deterioration of good early results (Chapple et al., 1991) and complications (Chapple et al., 1991; Murray et al., 1986), transvesical phenol is now seldom used. A more direct denervation is supratrigonal bladder transection. In patients with instability or hyperreflexia, 69% became symptom free and 19% improved (Mundy, 1983). U ro dy namics in 68 showed that of 40 who were symptom free, 14 were stable and 26 were less unstable, whereas of 28 poor responders, 8 were stable, 6 had stress incontinence, and the rest were unchanged (Mundy, 1983). Thus, relief of symptoms and stability correlated much less well than after some behavioural treatments or electrostimulation. The results of endoscopic transection were poor (Lucas and Thomas, 1987). Transection is rarely performed now. Selective blockade, usually of S3, sought to reduce unstable contractions and increase bladder capacity without sig nificantly affecting urethral pressure (Torrens, 1974). Motor denervation of the bladder was then attempted by selective anterior root neurectomy; of nine patients, instability was reduced in eight (Torrens, 1974). Longer followup, however, showed that incontinence and unstable contractions recurred frequently (Tarring et al., 1988). In hyperreflexia, after both sacral anterior root stimulation to improve bladder emptying and deafferentation to interrupt the micturition reflex arc, bladder capacity increased, hyperreflexia was abolished, and this was associated with continence (Gasparini et al., 1992). Deafferentation thus may be preferable to decentralisation in hyperreflexia, although it is clearly inappropriate for neurologically intact patients. In a huge series of patients who underwent the current technique of augmentation cystoplasty, clam ileocystoplasty (Bramble, 1990), for either instability or hyperreflexia, there were good results in 94% (McInemey et al., 1991). Potential disadvantages, along with the hazards of a laparotomy and small bowel anastomosis, include the need for intermittent self-catheterisation, metabolic disturbance, and late tumour formation, so the excellent incontinence control comes at a price. As with transection, a good outcome and reversion to stability correlate poorly (Sethia et al., 1991), implying that the operation may work simply by reducing the efficiency of pressure generation. In view of the drawbacks of the clam procedure, auto-augmentation, or detrusor myectomy, has been developed. This involves extraperitoneal excision of a patch of bladder wall over the dome, down to, but not including, urothelium, producing a pseudodiverticulum, which increases bladder capacity markedly (Stiihrer et al., 1995). Although the early results are promising (StGhrer et al., 1995), and it is a simpler proce-

W. H. Turner and A. F. Brading dure than the clam, it remains to be seen whether it proves as effective and safer.

10. CONCLUSION During the last two decades, an enormous amount of clinical and scientific data on the lower urinary tract has been gathered. Unfortunately, the accumulated knowledge has not been translated yet into significantly improved care of patients with functional lower urinary tract disorders. Why is this? As evident in this review, we now know a fair amount about the properties of the detrusor smooth muscle and how this changes in diseased or abnormal states. Theoretically, this should provide targets for treatment. However, much of this information has been obtained from animal studies, and often by basic scientists who may be more interested in the changes themselves than their aetiology or relevance in the whole animal or to the human. Even in the animal models of bladder dysfunction there is still considerable uncertainty as to the causes of the changes in the smooth muscle. From a practical point of view, it is important to know which of the clinical symptoms that need treating result from a change in smooth muscle properties and which result from the primary dysfunction that causes the change. There are a number of approaches for gathering data on the human lower urinary tract: symptoms, urodynamics, laboratory studies of isolated tissues. Unfortunately, the correlation between the results of these approaches is often less good than we would hope, which may reflect our inability to see their inherent limitations, as much as anything else. We are limited, after all, in what we can measure, and clinical studies are fraught with logistic and ethical problems. What we often fail to do, however, is to see where pieces of the picture cannot be added, other than by experimental studies, such as those outlined above in connection with the changes in bladder instability. Since most experimental studies have to be done on animals, clinicians are often reluctant, or not qualified, to carry them out. Failure to form sensible hypotheses about how instability comes about and to undertake experimental work to support or disprove them has slowed progress, since there is no incentive to change from a particular strategy for treatment, although quite another direction might be more appropriate. Our work suggests to us that by failing to ascertain whether instability really was due to overactivity in the micturition reflex arc, we have gone inappropriately in the direction of treatments designed to reduce excitatory input to the detrusor, which may actually predispose to instability, whereas agents that reduce detrusor excitability probably are more suitable. It, therefore, seems wise to develop a good understanding of the physiology, and probably the molecular biology, of the bladder’s K+ channels, to try to exploit them pharmacologically to treat bladder instability. There is no doubt that any truly effective agent would have massive application, surely an incentive to the pharmaceu-

101

Bladder Smooth Muscle in Health and Disease tical industry. between this needs

The key to this will be persistent

industry,

laboratory

scientists,

cooperation

and clinicians,

and

to be encouraged.

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